MX2008013528A

MX2008013528A - Method of inhibiting c kit kinase.

Info

Publication number: MX2008013528A
Application number: MX2008013528A
Authority: MX
Inventors: Christopher Flores; Shelley K Ballentine; Mark J Wall; Carl R Illig; M Jonathan Rudolph; Christopher J Molloy; Carl L Manthey; Jinsheng Chen; Kenneth Wilson; Sanath K Meegalla; Renee L Desjarlais
Original assignee: Jannsen Pharmaceutica N V
Priority date: 2006-04-20
Filing date: 2007-04-19
Publication date: 2008-10-29
Also published as: ES2458291T3; IL194846A0; EP2015748A2; CN102670605B; EP2015748B1; WO2007124369A2; ECSP088842A; EP2397138B1; KR101448052B1; MY147226A; BRPI0710542B8; ES2389678T3; NZ572200A; ZA200809874B; SG171592A1; EA200870454A1; CN101610768A; CR10450A; EP2397138A1; HK1124766A1

Abstract

A method of reducing or inhibiting kinase activity of C KIT in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to C KIT using a ompound of the present invention: Formula (I), or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. The present invention is further directed to methods for treating conditions such as cancers and other cell proliferative disorders.

Description

METHOD FOR INHIBITING THE C1NASA OF THE C-KIT CROSS REFERENCE TO RELATED REQUESTS This request claims the priority of the Provisional Application for E.U.A. for Patent No. 60 / 793,471, filed on April 20, 2006, the total description of which is incorporated herein in its entirety.

FIELD OF THE INVENTION The present invention relates to methods for reducing or inhibiting the kinase activity of C-KIT in a cell or in a subject, and the use of such methods for preventing or treating in a subject a cell proliferative disorder and / or related disorders. with the C-KIT.

BACKGROUND OF THE INVENTION Protein kinases are enzymatic components of the signal transduction pathways that catalyze the transfer of the terminal phosphate of ATP to the hydroxy group of the tyrosine, serine and / or threonine residues of the proteins. Thus, compounds that inhibit protein kinase functions are valuable tools for assessing the physiological consequences of protein kinase activation. Overexpression or Inappropriate expression of normal or mutant protein kinases in mammals has been a topic of extensive study and has been shown to play a significant role in the development of many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, rheumatoid arthritis , atherosclerosis, cardiovascular disease and cancer. The cardiotonic benefits of kinase inhibition have also been studied. In sum, inhibitors of protein kinases have a particular utility in the treatment of human and animal disease. The receptor of the tyrosine kinase C-KIT and its ligand, the Germinal Cell Factor (SCF) are essential for hematopoiesis, melanogenesis and fertility. The SCF acts at multiple levels of the hematopoietic hierarchy to promote the survival, proliferation, differentiation, adhesion and functional activation of the cells. It is of particular importance in mast cells and erythroid lineages, but it also acts on multipotential germ and progenitor cells, megakaryocytes and a subset of lymphoid progenitors (see, Int J Biochem Cell Biol. 1999 Oct; 31 (10): 1037-51). ). Sporadic mutations of C-KIT, as well as autocrine / paracrine activation mechanisms of the SCF / C-KIT pathway have been implicated in a variety of malignancies. Activation of C-KIT contributes to metastases, improving tumor growth and reducing apoptosis. In addition, C-KIT is frequently mutated and activated in gastrointestinal stromal tumors (GIST), and activation mediated by the ligand of C-KIT is present in some lung cancers (see, Leuk Res. 2004 May; 28 Suppl V.S1-20). The C-KIT receptor is also expressed in more than 10% of blasts in 64% of de novo acute myelogenous leukemias (AML) and 95% of relapsed AML. C-kit mediates proliferation and antiapoptotic effects in AML (see, Curr Hematol Rep. 2005 Jan; 4 (1): 51-8). The expression of C-Kit has been documented in a wide variety of human malignancies, including mastocytosis, mast cell leukemia, gastrointestinal stromal tumors, natural killer cytolytic lymphoma / T-cell lymphoma, seminoma, dysgerminoma, thyroid carcinoma; small cell lung carcinoma, malignant melanoma, adenoid cystic carcinoma, ovarian carcinoma, acute myelogenous leukemia, anaplastic large cell lymphoma, angiosarcoma, endometrial carcinoma, ALL of pediatric T lymphocytes, lymphoma, breast carcinoma and prostate carcinoma. See, Heinrich, Michael C. et al. Review Article: Inhibition of KIT Tyrosine Kinase Activity. A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies. Journal of Clinical Oncology, Vol 20, No 6 (March 15), 2002: pp 1692-1703.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for reducing or inhibiting the activity of the C-KIT kinase in a cell or in a subject, and the use of such methods for preventing or treating in a subject a cell proliferative disorder and / or disorders related to C-KIT. Other features and advantages of the invention will become apparent from the following detailed description of the invention and the claims.

DETAILED DESCRIPTION OF THE INVENTION The terms "comprising", "including" and "containing" are used in the present in their non-limited open sense.

Abbreviations As used herein, the following abbreviations are intended to have the following meanings (additional abbreviations are provided where they are needed through the Specification). ATP adenosine triphosphate Boc or BOC tert-butoxycarbonyl DCM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide DIEA diisopropylethylamine EDCI 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid EtOAc ethyl acetate FP polarization with fluorescence HOBT or HOBt 1-hydroxybenzotriazole hydrate LC / MS (ESI) liquid chromatography / mass spectrum (ionization with electropartum) MeOH methyl alcohol NMR nuclear magnetic resonance RT room temperature TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Definitions The term "alkyl" refers to both straight and branched chain radicals of up to 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. The term "hydroxyalkyl" refers to both straight and branched chain radicals of up to 6 carbon atoms, in which one hydrogen atom has been replaced with an OH group.

The term "hydroxyalkylamino" refers to a hydroxyalkyl group, in which a hydrogen atom of the carbon chain has been replaced with an amino group, wherein the nitrogen is the point of attachment to the rest of the molecule. The term "cycloalkyl" refers to a saturated or partially unsaturated ring composed of 3 to 8 carbon atoms. Up to four alkyl substituents may be optionally present in the ring. Examples include cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and 4,4-dimethylcyclohexenyl. The term "dihydrosulfonopyranyl" refers to the following radical: The term "hydroxyalkyl" refers to at least one hydroxyl group attached to any carbon atom along an alkyl chain. The term "aminoalkyl" refers to at least one primary or secondary amino group attached to any carbon atom along an alkyl chain, wherein an alkyl group is the point of attachment to the remainder of the molecule. The term "alkylamino" refers to an amino with an alkyl substituent, wherein the amino group is the point of attachment to the remainder of the molecule.

The term "dialkylamino" refers to an amino with two alkyl substituents, wherein the amino group is the point of attachment to the rest of the molecule. The term "heteroaromatic" or "heteroaryl" refers to aromatic ring systems of 5 to 7 monocyclic members or 8 to 10 bicyclic members, any ring of which may consist of one to four heteroatoms selected from N, O or S, in where the nitrogen and sulfur atoms can exist in any allowed oxidation state. Examples include benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl and thienyl. The term "heteroatom" refers to a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen and sulfur atoms can exist in any permitted oxidation states. The term "alkoxy" refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy. The term "arite" refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring. Examples include benzene, biphenyl and naphthalene.

The term "aralkyl" refers to a C 1-6 alkyl group that contains an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl. The term "sulfonyl" refers to the group -S (0) 2Ra, wherein Ra is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. A "sulfonylating agent" adds the group -S (O) 2Ra to a molecule.

Formula I The present invention comprises methods for using the compounds of Formula I (referred to herein as "the compounds of the present invention"): I or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl) , -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; W is pyrrolyl (including 1 H-pyrrol-2-yl), imidazolyl, (including 1 / - / - imidazol-2-yl), isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl (including furan-2) ilo), any of which can be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl can contain a substitution with -Cl, -CN, - N02, -OMe or -CF3, connected to any other carbon; R 2 is cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and alkyl of C (i .3) (including 4,4-dimethylcyclohexenyl, 4-methylcyclohexenyl, 2-methylthiophenyl, 3-methylthiophenyl), with the proviso that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is Z is CH or N; D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti-; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or a radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not being -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxyethylamino), (hydroxyalkyl) 2-amino, hydroxyalkyl (alkyl) amino (including 1-hydroxyethyl-2-yl (methyl) amino), alkylamino (including methylamino), aminoalkyl (including 2- aminoisopropyl), dihydroxyalkyl (including 1,3-dihydroxyisopropyl, 1,2-dihydroxyethyl), alkoxy (including methoxy), dialkylamino (including dimethylamino), hydroxyalkyl (including 1-hydroxy-2-yl), -COOH, -CONH2, - CN, -SO2-alkyl-R4 (including -SO2CH3), -NH2, or a 5- or six-membered ring containing at least one N heteroatom and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5 or 6 membered ring can be saturated, partially unsaturated or aromatic (including piperidinyl, morpholinyl, imidazolyl and pyridyl), wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide (including pyridyl N oxide), and the 5 or 6 member ring can be optionally substituted with methyl, halogen, alkylamino or alkoxy (including 1-methylimidazolyl), R3 may also be absent, with the proviso that R3 is not absent when E is nitrogen; R4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl.

Modalities The embodiments of the present invention include a compound of Formula I, wherein: a) A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH ( alkyl), -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; b) A is phenyl; c) W is pyrrolyl (including 1 / - / - pyrrol-2-yl), imidazolyl, (including 1 H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl (including furan- 2-yl), any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl may contain a substitution with -Cl, -CN , -NO2, -OMe or -CF3, connected to any other carbon; d) W is furan-2-yl, 1 H-pyrrol-2-yl or 1 H-imidazol-2-yl, any of which may be substituted at carbons 4 or 5 with -CN; e) W is 3H-2-imidazolyl-4-carbonitrile or 5-cyano-1 H-pyrrol-2-yl; W is 3H-2-imidazolyl-4-carbonitrile; 9) R 2 is cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and alkyl of C (i_3) (including 4,4-dimethylcyclohexenyl, 4-methylcyclohexenyl, 2-methylthiophenyl, 3-methylthiophenyl), with the proviso that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; h) R2 is cycloalkyl (including cyclohexenyl, cyclopentenyl), which may be substituted with one or two C (1-3) alkyl (including 4,4-dimethylcyclohexenyl, 4-methylcyclohexenyl); i) R2 is cyclohexenyl, which may be substituted with one or two alkyl j) R 2 is cyclohexenyl, 4,4-dimethylcyclohexenyl or 4-methylcyclohexenyl; k) R2 is cyclohexenyl; 0 X is Z is N; Z is CH; q) D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; r) D1 and D2 are each hydrogen; s) D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; t) D3 and D4 are each hydrogen; u) D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; v) Ra and Rb are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; w) E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or a cyclic amino radical, wherein the point of attachment to E is N; x) E is N, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 is an amino group or a cyclic amino radical, where the binding point is E is N; y) Qa is absent, is -CH2-, -CH2CH2- or C (O); z) Qa is absent, is -CH2CH2- or C (O); aa) Qa is absent or is C (O); bb) Qa is C (O); ce) Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of attachment to Qb is N; dd) Qb is absent, is -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O); ee) Qb is absent or is C (O), with the proviso that Qb may not be C (O) if Qa is C (O); ff) R3 is hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxyethylamino), (hydroxyalkyl) 2-amino, hydroxyalkyl (alkyl) amino (including 1-hydroxyethyl-2-yl (methyl) amino), alkylamino (including methylamino), aminoalkyl (including 2-aminoisopropyl), dihydroxyalkyl (including 1,3-dihydroxyisopropyl, 1,2-dihydroxyethyl), alkoxy (including methoxy), dialkylamino (including dimethylamino), hydroxyalkyl (including -hydroxy-2-yl), -COOH, -CONH2, -CN, -SO2-alkyl-R4 (including -S02CH3 ), -NH2, or a 5 or 6 membered ring containing at least one N heteroatom and may optionally contain an additional heterophore selected from S, S02, N and O, and the 5 or 6 membered ring may be saturated, partially unsaturated or aromatic (including piperidinyl, morpholinyl, imidazolyl and pyridyl), wherein the aromatic nitrogen in the 5- or 6-membered ring is present as N-oxide (including pyridyl-N-oxide), and the 5- or 6-membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy (including 1-methylimidazolyl); R3 may also be absent, provided that R3 is not absent when E is nitrogen; gg) R3 is hydrogen, phenyl, 2-hydroxyethylamino, 1-hydroxyethyl-2-yl (methyl) amino, methylamino, 2-aminoisopropyl, 1,3-dihydroxyisopropyl, 1,2-dihydroxyethyl, methoxy, dimethylamino, 1-hydroxyethyl 2-yl, -COOH, -CONH2, -CN, -SO2-, -SO2CH3), -NH2, piperidinyl, morpholinyl, imidazolyl, pyridyl, pyridyl N oxide), or 1-methylimidazolyl; hh) R3 is alkylamino (including methylamino), dialkylamino (including dimethylamino), or -SO2-alkyl-R4 (including -SO2CH3); ii) R3 is methylamino, dimethylamino or -SO2CH3; jj) R3 is dimethylamino; kk) R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl; and II) R4 is hydrogen; and all combinations of a) to II), inclusive, here above. Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl), -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which can be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1, 2,4- triazolyl or furanyl may contain a substitution with -Cl, -CN, -NO2, -OMe or -CF3, connected to any other carbon; R2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and C (i -3) alkyl, with the proviso that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is and is oriented for with respect to -NHCO-W; Z is CH or N; D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3l where -CH3 can be oriented relatively syn or anti; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Q is absent, and R3 in an amino group or a radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not being -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5- or 6-membered ring can be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl. Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1, 2, 4-triazolyl or furanyl may contain a substitution with -Cl, -CN, -NO2, -OMe or -CF3, connected to any other carbon; R2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, tetrahydropyridyl or dihydropyranyl, any of which may be substituted independently with one or two of each of the following: chlorine, fluorine and C (1.3) alkyl, provided that that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is and is oriented for with respect to -NHCO-W; Z is CH or N; D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or a radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not being -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a ring of 5 or six members containing at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, SO ?, N and O, and the 5- or 6-membered ring may be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5- or 6-membered ring is present as N-oxide, and the 5- or 6-membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl. Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl; W is 3H-2-imidazolyl-4-carbonyltryl; R 2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be substituted independently with one or two of each of the following: chlorine, fluorine and C (1-3) alkyl; with the proviso that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is and is oriented for with respect to -NHCO-W; Z is CH or N; D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or a radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional condition that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5- or 6-membered ring can be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy, R3 may also be absent, provided that R3 is not absent when E it's nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl. Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl; W is 3 / - / - 2-imidazolyl-4-carbonitrile; R2 is cyclohexenyl, which may be substituted with one or two methyl groups; X is and is oriented for with respect to -NHCO-W; Z is CH or N; D1 and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Q is absent, and R3 in an amino group or a radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5 or 6 membered ring may be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5- or 6-membered ring is present as N-oxide, and the 5- or 6-membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl. Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl; W is 3 / - / - 2-imidazolyl-4-carbonitrile; R2 is cyclohexenyl, which may be substituted with one or two methyl groups; X is and is oriented for with respect to -NHCO-W; Z is CH; D1 and D2 are each hydrogen; D3 and D4 are each hydrogen; D5 is -CH3, wherein -CH3 can be oriented relatively syn or anti, E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), with the additional condition that Qb may not be - NH- if R3 is an amino group or a cyclic amino radical, wherein the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-CH3, -NH2, pyridyl, pyridyl-N-oxide or morpholinyl.

Other preferred embodiments of Formula I are those wherein: A is phenyl or pyridyl; W is 3H-2-imidazolyl-4-carbonitrile; R2 is cyclohexenyl, which may be substituted with one or two methyl groups; X is Examples of the compounds of Formula I include: [4- (4-methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-yl) -phenyl] -amide 5-cyano acid -furan-2-carboxylic acid and 5-Cyano-furan-2-carboxylic acid [4- (4-methyl-piperazin-1-yl) -2- (2-methyl-thiophen-3-yl) -phenyl] -amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Additional examples of the compounds of Formula I include: [4- (1-acetyl-piperidin-4-yl) -2- (1, 2,5,6-tetrahydro-pyridin-3-yl) - phenyl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, [2-cyclohex-1-enyl-4- (1,1-dioxo-hexahydro-6-thiopyran-4-yl) -phenyl) ] - 4-cyano-1 H-imidazole-2-carboxylic acid amide, 5-cyano [2-cyclohex-1-enyl-4- (4-methyl-piperazin-1-yl) -phenyl] -amide] -furan-2-carboxylic acid, [2- (3,6-dihydro-2H-pyran-4-yl) -4- (4-methyl-piperazin-1-yl) -phenyl] -amide of 5-cyano- furan-2-carboxylic, [2- (1, 1-dioxo-1, 2,3,6-tetrahydro-1? 6 - ????? G3? -4 - ??) - 4 - ??? ßp ??? - 4 4-cyano-1 H-imidazole-2-carboxylic acid -? - phenyl] -amide, [4- (1-acetyl-piperidin-4-yl) -2- (1,1-dioxo-1,2) 4-cyano-1 H-imidazole-2-carboxylic acid, 3,6-tetrahydro-n6-thiopyran-4-yl) -phenyl] -amide, [2'-methyl-5- (4-methyl-piperazine- 5-cyano-furan-2-carboxylic acid 1-yl) -biphenyl-2-yl] -amide and [2'-fluoro-5- (4-methyl-piperazin-1-yl) -biphenyl-2-yl ] -5-cyano-furan-2-carboxylic acid amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Additional examples of the compounds of Formula I are: (4- {4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl}. . -piperidin-1-yl) -acetic acid, 4- (1-carbamoylmethyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1 H-imidazole-2 -carboxylic acid, 4-cyano-1 H-imidazole-2-carboxylic acid [2- (4-methyl-cyclohex-1-enyl) -4-piperidin-4-yl-phenyl] -amide. { 2-cyclohex-1-enyl-4- [1 - (2-hydroxy-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, [2- (4-methyl-cyclohex-1-enyl) -4- (1-pyridin-2-ylmethyl-piperidin-4-yl) - phenyl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 2-cyclohex-1-enyl-4- [1- (2-hydroxy-1-hydroxymethyl-ethyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 4- [1- (2-cyano-ethyl) -piperidin-4-yl] -2-cyclohex-1-enyl-phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 2-Cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, 4-cyano-1 H-imidazole-2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl-amide -carboxylic,. { 2-cyclohex-1-enyl-4- [1- (2-methanesulfonyl-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, [4-Cyano-1 H-imidazole-2-cyclohex-1-enyl-4- (1-pyridin-2-ylmethyl-p-4-yl-4-yl) -phenyl] -amide] carboxyl,. { 2-cyclopent-1-en-l-4- [1- (1-methyl-1 H-imidazol-2-yl-methyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, 4-cyano-1 H-imidazole (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl) -amide 2-carboxylic acid, 4-cyano-1 H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide, [2-cyclohex-1-enyl- 4- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -phenyl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid and [4- 4-Cyano-1 H-pyrrole-2-carboxylic acid (1-acetyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts of the same. Other examples of the compounds of Formula I are: { 2-cyclohex-1-enyl-4- [1- (1-oxy-pyridine-3-carbonyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-H-imidazole-2-carboxylic acid,. { 2-cyclohex-1-en-l-4- [1 - (1-oxy-pyridin-4-carbonyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-H-imidazole-2-carboxylic acid,. { 2-cyclohex-1-enyl-4- [1 - (3-morpholin-4-yl-propionyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, 4-amide. { 4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl} -piperidin-1 -carboxylic, . { 2-Cyclohex-1-enyl-4- [1 - (pyridine-3-carbonyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, (2-hydroxy-ethyl) -amide of 4-acid. { 4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl} -piperidin-1 -carboxylic,. { 2-cyclohex-1-enyl-4- [1 - (2-3H-imidazol-4-yl-acetyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 2-Cyclohex-1-enyl-4- [1 - (2-pyridin-4-yl-acetyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, (2-cyclohex-1-enyl-4- { 1 - [2- (1-methyl-1 H-imidazol-4-yl) 4-cyano-1 H-imidazole-2-carboxylic acid-acetyl] -piperidin-4-yl} -phenyl) -amide ,. { 2-Cyclohex-1-enyl-4- [1 - (2-pyridin-3-yl-acetyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 2-cyclohex-1-enyl-4- [1- (2-methanesulfonyl-acetyl) -piperidin-4-yl] -phenyl} -amide of 4-cyano-1 H-imidazole-2-carboxylic acid,. { 2-cyclohex-1-enyl-4- [1 - (2-pyridin-2-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide and 4- (1-acetyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano- 1 H-imidazole-2-carboxylic acid, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Another example of the compound of Formula I is: [2-cyclohex-1-enyl-4- (1-. {2 - [(2-hydroxy-ethyl) -methyl-amino] -acetyl} -piperidin-4 4-cyano-1 H-imidazole-2-carboxylic acid -yl) -phenyl] -amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Another example of the compound of Formula I is: { 2-Cyclohex-1-enyl-4- [1- (2-dimethylamino-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Another example of the compound of Formula I is: { 2-cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Still other examples of the compounds of Formula I are: trifluoroacetic acid salt of the. { 4- [1 - (3-amino-3-methyl-butyryl) -piperidin-4-yl] -2-cyclohex-1-enyl-phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, Bis-trifluoroacetic acid salt of 4H- (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide 1, 2,4] -triazole-3-carboxylic acid, Trifluoroacetic acid salt of 5-chloro-4H- [1-cyclohex-1-enyl-4-piperidin-4-yl-phenyl] -amide. , 2,4] -triazole-3-carboxylic acid, Bis-trifluoroacetic acid salt of [2-cyclohex-1-enyl-4- (cis-2,6-dimethyl-piperidin-4-yl) -phenyl] -amide of 5-cyano-1 H-imidazole-2-carboxylic acid, Exit of bis-trifluoroacetic acid from 5-cyano-1 H-imidazole-2-cyclohex-1-enyl-4- (trans-2,6-dimethyl-piperidin-4-yl) -phenyl] -amide -carboxylic,. { 2-cyclohex-1-enyl-4- [1- (R) - (+) - (2,3-dihydroxy-propionyl) -piperidin-4-yl] -phenyl} - 5-cyano-1 H-imidazole-2-carboxylic acid amide, [2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenyl] - trifluoroacetic acid salt 5-cyano-1 H-imidazole-2-carboxylic acid amide, [6 (4,4-dimethyl-cyclohex-1-ynyl) -1 ', 2', 3 ', 4' trifluoroacetic acid salt , 5'-6'-hexahydro- [2,4 '] bipyridinyl-5-yl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, trifluoroacetic acid salt of the. { 4- [1 - (2-amino-2-methyl-propionyl) -piperidin-4-yl] -2-cyclohex-1-enyl-phenol} -amide 5-cyano-1 H-imidazole-2-carboxylic acid and [e-cyclohex-1-ene-r ^ -metanesulfonyl-ethyl-1 '' 'S' ^ '. S'.e'-hexahydro- [2,4 '] bipyridinyl-5-yl] -amide of 5-cyano-1 H-imidazole-2-carboxylic acid, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. Additional examples of the compounds of Formula I are: { 2-cyclohex-1-enyl-4- [1 - (2-methylamino-acetyl) -pipendin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide, Salt of trifluoroacetic acid of [1 '- (2-dimethylamino-acetyl) -6- (4,4-dimethyl-cyclohex-1-enyl) -1 \ 2 \ 3 \ 4 \ 5 \ 6'-hexahydro- [ 2.4 4-cyano-1 H-imidazole-2-carboxylic acid bipyridinium and [6 (4,4-dimethyl-cyclohex-1-yl) -1 '- (2-methanesulfonyl-) trifluoroacetic acid salt ethyl) -1 \ 2 \ 3 \ 4, 15,, 6, -hexahydro- [2,4,] bipyridinyl-5-yl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid, and solvates , hydrates, tautomers and pharmaceutically acceptable salts thereof. As used herein, the term "the compounds of the present invention" should also include solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts As indicated, the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". The forms of pharmaceutically acceptable salts approved by the FDA. { Ref. International J. Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977, Jan, 66 (1), p1), include pharmaceutically acceptable acidic / anionic or basic / cationic salts.

Acidic / pharmaceutically acceptable anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, glycetate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate and triethyodide. The organic or inorganic acids also include and, in a non-exclusive manner, hydroiodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethane sulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexansulfamic, saccharinic or trifluoroacetic acids. The pharmaceutically acceptable basic / cationic salts include, and are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris (hydroxymethyl) aminomethane, tromethane or "TRIS"), ammonia. , benzathine, f-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH , N-methyl-D-glucamine, piperidine, potassium, potassium r-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate (SEH), sodium or zinc hydroxide .

Prodrugs The present invention also includes, within its scope, prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds that are easily convertible in vivo to an active compound. Thus, in the methods of treatment of the present invention, the term "administer" will encompass the means for treating, alleviating or preventing a syndrome, disorder or disease described herein, with the compounds of the present invention or a prodrug thereof. , which will obviously be included within the scope of the invention even if a given compound is not specifically described. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, "Desiqn of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Stereochemical Isomers One skilled in the art will recognize that some compounds of the present invention have one or more asymmetric carbon atoms in their structure. It is intended that the present invention include within its scope simple enantiomeric forms of the compounds of the present invention, racemic mixtures and mixtures of enantiomers in which an enantiomeric excess is present.

The term "single enantiomer" as used herein, defines all possible homochiral forms that the compounds of the present invention and their N oxides, addition salts, quaternary amines and physiologically functional derivatives may possess. The stereochemically pure isomeric forms can be obtained by applying principles known in the art. The diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and the enantiomers can be separated from one another by selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. The pure stereoisomers can also be prepared synthetically from appropriate stereochemically pure raw materials or using stereoselective reactions. The term "isomer" refers to compounds that have the same composition and molecular weight, but differ in physical and / or chemical properties. Such substances have the same number and class of atoms, but differ in structure. The structural difference can be in the constitution (geometric isomers) or in a capacity to rotate the plane of polarized light (enantiomers). The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. The enantiomers and diastereomers are examples of stereoisomers.

The term "chiral" refers to the structural feature of a molecule that makes it impossible to superimpose it on its mirror image. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of one another and that are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images. The symbols "R" and "S" represent the configuration of the substituents around the chiral carbon atoms. The term "racemate" or "racemic mixture" refers to the composition composed of equimolar amounts of two enantiomeric species, wherein the composition is devoid of optical activity. The term "homochiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which the homochiral molecule or the non-racemic mixture of the chiral molecules rotate a plane of polarized light. It will be understood that the various substituent stereoisomers, geometric isomers and mixtures thereof, used to prepare the compounds of the present invention, are commercially available, can be prepared synthetically from commercially available raw materials or can be prepared as isomeric mixtures and then obtained as resolved isomers using techniques well known to those of ordinary skill in the art. The isomeric descriptors "R" and "S" are used as described herein to indicate the configuration of the atom relative to a central molecule and are intended to be used as defined in the literature (IUPAC Recommendations for Fundamental Stereochemistry (Section E) , Pure Appl. Chem., 1976, 45: 13-30). The compounds of the present invention can be prepared as a single isomer, either by specific synthesis of the isomer or resolved from an isomeric mixture. Conventional resolution techniques include forming the free base of each isomer of an isomer pair using an optimally active salt (followed by fractional crystallization and regeneration of the free base), forming an ester or amide of each of the isomers of an isomeric pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of the raw material or a final product using preparative TLC (thin layer chromatography) or a chiral HPLC column.

Polymorphs and Solvates Further, the compounds of the present invention may have one or more polymorphous or amorphous crystalline forms and therefore, are intended to be included in the scope of the invention. In addition, the compounds can form solvates, for example, with water (ie, hydrates) or solvents common organic As used herein, the term "solvate" means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves several degrees of ionic and covalent bonds, including hydrogen bonds. In certain cases, the solvate will be capable of isolation, for example, when one or more of the solvent molecules are incorporated into the crystalline lattice of the crystalline solid. The term "solvate" is intended to encompass both solvates in the solution phase and insulables. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. It is intended that the present invention include within its scope solvates of the compounds of the present invention. Thus, in the methods of treatment of the present invention, the term "administer" will encompass means for treating, alleviating or preventing a syndrome, disorder or disease described herein with the compounds of the present invention or a solvate thereof, which would obviously be included within the scope of the invention even if they are not specifically described.

N oxides The compounds of the present invention can be converted to their corresponding N-oxide form following the procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Such a reaction of N oxidation can be carried out generally making react the raw material with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metals, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkylhydroperoxides, for example, f-butyl hydroperoxide . Suitable solvents are, for example, water, lower alcohols, for example, ethanol and the like, hydrocarbons, for example, toluene, ketones, for example, 2-butanone, halogenated hydrocarbons, for example, dichloromethane, and mixtures of such solvents.

Tautomeric forms The compounds of the present invention may also exist in their tautomeric forms. Such forms, although not explicitly stated in the present application, are intended to be included within the scope of the present invention.

Preparation of the compounds of the present invention During any of the processes for the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect the sensitive or reactive groups in any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Protectinq Groups, P. Kocienski, Thieme Medical Publishers, 2000; and T.W. Greene & P.G.M. Wuts, Protective Groups in Orqanic Synthesis, 3rd ed. Wiley Interscience, 1999. Protective groups can be removed at a convenient later stage using methods known in the art.

Preparation methods REACTION SCHEME 1 Reaction Scheme 1 illustrates the general methodology for the preparation of the compounds of Formula I. Compounds of Formula 1 -2 can be obtained by orthohalogenation, preferably bromination of the amino compounds of Formula 1-1, followed by reactions of metal-catalyzed coupling with boronic acids or boronate esters (Suzuki reactions, where R2M is R2B (OH) 2 or a boronic ester) or tin reagents (Stille reactions, where R2M is R2Sn (alkyl) 3) (for reviews, see N. Miyaura, A. Suzuki, Chem. Rev., 95: 2457 (1995), JK Stille, Angew. Chem, Int. Ed. Engl., 25: 508024 (1986) and A. Suzuki in Metal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Eds., Wiley-VCH, Weinheim (1988)). Compounds of formula 1-1 may be commercially available, or palladium mediated cross-coupling reactions described above may be used to generate the compounds of Formula 1 -1 from the raw material 1 -0. The preferred conditions for bromination of 1-1 are N-bromosuccinimide (NBS) in a suitable solvent such as A /, A / -dimethylformamide (DMF), dichloromethane (DCM) or acetonitrile. Metal-catalyzed couplings, preferably Suzuki reactions, can be carried out according to standard methodology, preferably in the presence of a palladium catalyst such as tetracis (triphenylphosphine) palladium (0) (Pd (PPh3) 4), an aqueous base such as aqueous Na 2 CO 3 and a suitable solvent such as toluene, ethanol, dimethoxyethane (DME) or DMF.

The compounds of Formula I can be prepared by reacting the compounds of Formula 1-2 with carboxylic acids WCOOH according to standard procedures for the formation of an amide bond (for a review, see: M. Bodansky and A. Bodansky , The Practice of Peptide Synthesis, Springer-Verlag, NY (1984)), or by reaction with WCOCI acid chlorides or activated WCO2Rq esters (wherein Rq is a leaving group such as pentafluorophenyl or N-succinimide). Preferred reaction conditions for coupling with WCOOH are: when W is a furan, oxalyl chloride in DCM with DMF as a catalyst to form the acid chloride WCOCI and then coupling in the presence of a trialkylamine such as DIEA; where W is a pyrrole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole-6-sulfonamidomethyl hydrochloride (HOBt); and when W is an imidazole, the preferred conditions are bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) and diisopropylethylamine (DIEA) in DCM. It is understood that the optional substitution present in ring A in Formula I may be present in the raw materials 1 -1 or 1 -3 and, in such cases, it would be carried out through the synthesis set forth in the Reaction Scheme. 1 . Alternatively, various substituents on the compounds of Formula I can be introduced in various manners described below to provide the optional substitution listed for Formula I. The leaving group "L- present on ring A in Formula 1 -0 or 1" -3, it can be replaced before or at any step during Reaction Scheme 1. When such outgoing groups (preferred way, fluorine or chlorine) are activated by the nitro group of Formula 1 -3 for nucleophilic attack, can be subjected to a direct nucleophilic aromatic substitution by an ammonia and azide anion or by amines, alcohols, thiols and other nucleophiles in the presence of a suitable base, such as K2CO3, A /, A / -diisopropylethylamine (DIEA) or NEt3. When the leaving group is suitable for metal-catalyzed couplings (preferably bromine or trifluoromethanesulfonyloxy), various cross-coupling reactions (such as Suzuki or Stille reactions as discussed above for the introduction of R2) can be performed. Other metal catalyzed coupling reactions that can be employed include aromatic and heteroaromatic amination and amidation (for reviews, see: SL Buchwald, et al, Top, Curr. Chem., 219: 131-209 (2001) and JF Hartwig in. Organopalladium Chemistry for Organic Synthesis, "Wiley Interscience, NY (2002). Additional metal-catalyzed cross-coupling reactions with 2,4,6-trimethyl-cyclotriboroxane can be employed if L-es is bromine, iodine or nitro-activated chlorine for generate the optional methyl substitution (see, M. Gray, et al, Tetrahedron Lett., 41: 6237-40 (2000).) In some cases, the initial substituents may be further derivated as described below to provide the final substitution. of Formula I. An alternate method for the introduction of the nitrogen-containing heterocyclic substituents on ring A is to form the heterocycle to starting from an amino group on ring A. The amino group may be present originally in the raw material in a protected or unprotected form or it may result from the reduction of a nitro group which may also be originally present in the raw or bonded material by a nitration reaction. In addition, the amino group can be formed by the reduction of an azide group which may be present in the raw material or can result from the nucleophilic aromatic substitution of a halide activated by the azide anion as mentioned above. The amino group can also result from the aromatic nucleophilic substitution of an activated halide (in, for example, a nitrohalo compound) by ammonia or by the anion of a protected ammonia equivalent, for example, t-butyl carbamate. If introduced in the protected form, the amine can be deprotected according to standard methods in the literature. (For examples of amine protecting groups and deprotection methods see Theodora W. Greene and Peter GM Wuts, John Wiley and Sons, Inc., NY (1991).) The ring formation reaction involves the treatment of the amino group of the aniline with an optionally substituted substituted dielectrophile, preferably, a dihalide or dicarbonyl compound, which results in two substitutions on the amino group to form an optionally substituted heterocycle. In the case of the dihalides, any of several suitable bases can be added as an acid scavenger, such as potassium carbonate, sodium hydroxide, or, a trialkylamine such as triethylamine. Thus, treatment with a bis (2-haloethyl) amine such as bis (2- chloroethyl) amine ob (2-bromoethyl) amine would provide a piperazine ring (see, for example, J. Med. Chem., 29: 640-4 (1986) and J. Med. Chem., 46: 2837 (2003)). Optional substitution in the amine nitrogen of the reagent would incorporate the optional substitution of the terminal amine of the piperazine. For example, treatment with A /, A / -bis (2-chloroethyl) annol would provide a / V-phenylpiperazino group. Treatment with a bis (2-haloethyl) ether or bis (2-haloethyl) thioether would provide a morpholine or thiomorpholine ring, respectively. Another alternative method for direct substitution to introduce the heterocyclic substituents on ring A is to form the heterocycle from an aldehyde (ie, from a formyl group on ring A). The formyl group may be originally present in the raw material in a protected or unprotected form or may result from any of several formylation reactions known in the literature, including a Vilsmeier-Haack reaction (for a review of the formylation chemistry, see: GA Olah, et al, Chem Rev., 87. (1987)) or para-formylation of nitroaromatics (see: A. Katritsky and L. Xie, Tetrahedron Lett., 37: 347-50 (1996)) . Finally, it is understood that the compounds of Formula I can be derivatized further. The protecting groups of the compounds of Formula I can be removed according to standard synthetic methodologies (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc., NY (1991)), and can then be derivatized. additional. Examples of further derivatization of the compounds of I include, but are not limited to: when the compounds of Formula I contain a primary or secondary amine, the amine can be reacted with aldehydes or ketones in the presence of a reducing agent, such as sodium triacetoxyborohydride (see, Abdel-Magid J. Org. Chem. 61, pp. 3849-3862, (1996)), for reductive renting; with acid chlorides or carboxylic acids and a reagent that forms an amide bond as described above to form amides; with sulfonyl chlorides to form sulfonamides; with isocyanates to form ureas; with aryl or heteroaryl halides in the presence of a palladium catalyst as described above (see the above references of Buchwald and Hartwig) to form an aryl and heteroarylamines. further, when the compounds of Formula I contain an aryl halide or a heteroaryl halide, these compounds can be subjected to metal catalyzed reactions with boronic acids (for example, Suzuki or Stille couplings as described above), or, amines or alcohols (Couplings of the Buchwald or Hartwig type, see previous references by Buchwald and Hartwig). When the compounds of Formula I contain a cyano group, this group can be hydrolyzed to amides or acids under acidic or basic conditions. The basic amines can be oxidized to N oxides and conversely the N oxides can be reduced to basic amines. When the compounds of Formula I contain a sulphide, either acyclic or cyclic, the sulfide can be further oxidized to the corresponding sulfoxides or sulfones. Sulfoxides can be obtained by oxidation using an appropriate oxidant, such as an equivalent of (mefa-chloroperbenzoic acid) MCPBA or by treatment with NalO4 (see, for example, J. Regan, et al, J. Med. Chem., 46: 4676-86. (2003)) and sulfones can be obtained using two equivalents of MCPBA or by treatment with N-oxide of 4-methylmorpholine and tetroxide of catalytic osmium (see, for example, PCT application WO 01/47919).

REACTION SCHEME 2a where Z is CH e eacc n 1 Reaction Scheme 2a illustrates a route for the compounds of Formula I. F represents -NQaQbR3-, -O-, S, SO or SO2 and AA represents -NH2 or -NO2. D and D2 are shown for illustrative purposes only; it is recognized by those skilled in the art that D5, D6, D7, D8 may also be present. Ketones of formula 2-1 can be converted to a vinyl triflate of formula 2-2 by treatment with a non-nucleophilic base such as LDA, and then trapping the resulting enolate with a triflating reagent such as trifluoromethanesulfonic anhydride or preferably N-Phenyltrifluoromethanesulfonimide. The Suzuki coupling of boronic acids or boronate esters of formula 2-3 to vinyl triflates of formula 2-2 can provide compounds of formula 2-4, wherein Z is C. { Synthesis, 993 (1991)). For compounds of formula 2-4, treatment with Pd / C can reduce both the olefin (and the nitro if AA is NO2) to provide Z is CH, AA is NH2. The compounds of formula 2-4, wherein F represents -SO2, can be prepared from the compounds of formula 2-4, wherein AA is -NO2 and F is a sulfide (F is -S-) by oxidation with MCPBA or other methods described in Reaction Scheme 1. The nitro group can then be reduced with Pd / C to reduce both the nitro and the olefin. The compounds of formula 2-4 (AA is NH 2), are then converted to the compounds of Formula 2-5 (which also represent the compounds of Formula I if no further modifications are required), as described in the Reaction Scheme 1 .

The compounds of formula 2-5 can be further modified to provide additional compounds of Formula I. For example, in cases where F is -NQaQbR3-, QaQb is a direct bond, and R3 represents a protecting group of BOC (C02tBu) , the BOC group can be removed according to standard methodology such as trifluoroacetic acid (TFA) in DCM (Greene and Wuts, ibid.), to provide a secondary amine that can be further derivatized to provide the compounds of Formula I. The additional derivation includes, but is not limited to: reactions with aldehydes or ketones in the presence of a reducing agent such as sodium triacetoxyborohydride to provide the compounds of Formula II, wherein F is -NCH2R3 (AF Abdel-Magid, ibid.); with acid chlorides or with carboxylic acids and a reagent forming an amide bond (as described in Reaction Scheme 1), to provide compounds of Formula II, wherein F is -NCOR3; with sulfonyl chlorides (as described in Reaction Scheme 1), to provide compounds of Formula I, wherein F is -NS02Ra; with isocyanates (as described in Reaction Scheme 1), to provide compounds of Formula II, wherein F is -NCONRaRb; or undergoing metal-catalyzed substitution reactions as set forth in Reaction Scheme 1 to provide the compounds of Formula I, wherein F is -NR3. (S. L. Buchwald, et al, ibid., J. H. Hartwig, ibid.). For the previous example, Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

REACTION SCHEME 2b Reaction Scheme 2b illustrates a modification of Reaction Scheme 2a to synthesize partially unsaturated compounds of Formula I. E represents -NQaQbR3-, -O- (D1 and D2 are H), -S- (D1 and D2 are H), - (D1 and D2 are H) or -S02- (D1 and D2 are H), and RAA represents -NH2 or -N02. The compounds of formula 2-4 are prepared as shown in Reaction Scheme 2. If RAA is -N02, the nitro group should be reduced by a method that does not reduce olefins, such as iron chloride and ammonium. If RAA of formula 2-4 is an amino group, then no step is necessary and compounds of formula 2-4 are also compounds of formula 2-7. To prepare the compounds of formula 2-7, wherein E is -SO2- or -SO-, the oxidation of the sulfide should be carried out in compound 2-4, where RAA is -NO2 as described above, followed by the reduction of nitro.

REACTION SCHEME 3 Reaction Scheme 3 illustrates the preparation of intermediates for the synthesis of the compounds of Formula I, wherein ring A is pyridyl, and R 5 is the optional substitution on ring A or one of the heterocyclic substituents as defined in Formula I. K is NH2 or other functional groups such as NO2, COOH or COOR, which may eventually be converted to an amino group by methods known in the literature, such as reductions for N02 (as discussed for Reaction Scheme 1). ) or the Curtius rearrangement for COOH (for a review, see Organic Reactions, 3: 337 (1947)). L3 and L4 are halogens. (K is COOH, can also be formed from K is COOR by a catalyzed hydrolysis with base or simple acid). In general, the selectivity and the order to introduce R2 and R5 can be achieved by the relative reactivity of the halogen L3 and L4 chosen in the compound (3-1), the intrinsic selectivity of the heterocycle and / or the reaction conditions employed. An example of using the relative reactivity of the halogens L3 and L4 in the selective introduction of R2 and R5, would include the situation where the compounds of Formula 3-1, wherein L3 is a fluorine group and L4 is a bromine group, the selective displacement of the group Fluorine by a nucleophile can be achieved followed by replacement of the remaining bromine group by substitution chemistry catalyzed by a metal (such as the cross-coupling reactions of Suzuki or Stille as further discussed below). Similarly, compounds of Formula 3-1, wherein one of L3 and L4 is an iodine group and the other is a bromo or chloro group, the selective chemistry of metal-catalyzed substitution (such as cross-coupling reactions) of Suzuki or Stille or Buchwaid / Hartwig aminations as discussed further below) in the iodo group, can be achieved after replacement of the remaining bromine or chlorine group by another metal catalyzed substitution reaction. As illustrated in Reaction Scheme 3, the outgoing group L3 in Formula 3-1 can be substituted first to obtain compounds of Formula 3-3 or the leaving group L4 can be substituted first to obtain the compound of Formula 3-2. Compounds 3-2 or 3-3 may then react to displace L3 or L4 to provide the compound of Formula 3-4. Thus, a direct nucleophilic displacement or a metal-catalyzed amination of the compound of Formula 3-1 with a secondary amine, ammonia or a protected amine such as re-butyl carbamate. (for a review, see Modern Amination Methods: Ricci, A., Ed., Wiley-VCH: Weinheim, 2000), can be used to introduce R5 into Formulas 3-2 or 3-3, where R5 is an amine primary or secondary, an amino group (NH2) and an equivalent amine or a protected amino group. The metal-catalyzed coupling of compound 3-1 with boronic acids or boronate esters (Suzuki reaction, M is a boronic acid group or a boronate ester group) or with organotin compounds (Stille reaction, M is SnR3 wherein R is alkyl and the other substituents are as defined above, as described in Reaction Scheme 1, the compounds of Formulas 3-2 or 3-3 may provide Compound 3-2 may further be converted to the compound 3-4 by a metal-catalyzed Suzuki or Stille coupling as described above, L4 in compound 3-3 can also be subsequently substituted with R5 to obtain the compounds of Formula 3-4, again, by direct nucleophilic substitution or a metal-catalyzed reaction with a nucleophile or by the same metal catalyzed cross-coupling reaction as described above When R5 in the formulas (3-2, 3-3 or 3-4) s a protected amine and K is not an amino group, it can be deprotected to unmask the amino functionality. This amino functionality can then be further derived as described in Reaction Scheme 1. When the K group in Formula 3-4 is not an amino group (such as the functionality described above), it can be converted to an amino group according to the methods known in the literature (see, for example, Comprehensive Organic Transformations: Larock, RS, Wiley and Sons Inc., USA, 1999), and the resulting amine 3-5 can be employed in amide bond formation reactions as described in the Reaction Scheme (1), to obtain the compounds in Formula I. When K in Formula 3-4 is an amino group, it can be used directly in the coupling of the amide as described above.

REACTION SCHEME 4a 4-1 4-2 4-3 4-4 REACTION SCHEME 4b Reaction Schemes 4a and 4b illustrate the preparation of the intermediates to be modified further according to Reaction Scheme 3, starting from a monohalo substituted compound of Formulas 4-1 and 4-5, introducing the second leaving group after the replacement of the first has been completed. These can also be used for the synthesis of the compounds of Formula I, wherein ring A is a pyridine and R 5 is the optional substitution on Ring A or one of the heterocyclic substituents. As in Reaction Scheme 3, the remaining positions in the pyridine ring can be substituted as described in Formula I. K is NH 2 or other functional groups such as NO 2, COOH or COOR that can finally be converted to an amino group by the methods known in the literature, such as Curtius reductions or rearrangement as described in Reaction Scheme 3. L3 and L4 are halogens. In these compounds, T is H or is a functional group such as OH that can be converted to leaving groups L3 or L4, such as halogen, triflate or mesylate by methods known in the literature (see, for example, Nicolai, E. , et al., J. Heterocyclic Chemistry, 31, (73), (1994)). Displacement of L3 in the compound of Formula 4-1 or L4 in Formula 4-5 by the methods described in Reaction Scheme 3, can provide the compounds of Formulas 4-2 and 4-6. At this point, the substituent T of the compounds 4-2 or 4-6 can be converted to a leaving group L4 or L3 (preferably a halogen) by standard methods to provide the compounds of the formulas 4-3 and 4- 5. For example, when T is OH, the preferred reagents for carrying out this transformation are thionyl chloride, PCI5, POCI3 or PBr3 (see, for example, Kolder, den Hertog., Red. Trav. Chim. Pays-Bas; 285, ( 1953) e Iddon, B, et. al., J. Chem. Soc. Perkin Trans. 1., 1370, (1980)). When T is H, it can be directly halogenated (preferably brominated), to provide the compounds of Formulas 4-3 or 4-7 (see, for example, Canibano, V. et al., Synthesis, 14, 2175 , (2001)). Preferred conditions for bromination are NBS in a suitable solvent such as DCM or acetonitrile. The compounds of Formulas 4-3 or 4-7 can be converted to the compounds of Formulas 4-4 or 4-8 by introducing the remaining groups R2 or R5, respectively, by the methods described above, and then into the compounds of Formula I, by the methods described in Reaction Scheme 3 for the conversion of the compounds of Formulas 3-4 and 3-5 to the compounds of Formula I. The representative compounds of the present invention and their synthesis are presented in the following graph and the later examples. The following is for exemplary purposes only, and is not intended in any way to limit the invention. Preferred compounds of the present invention are Examples 5, 17, 23, 34, 38 and 51. Preferred examples of the C-KIT inhibitors are 51 a, 48, 52, 55 and 26.

Structure Name 5-cyano-furan-2-carboxylic acid 4- (4-methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-yl) -phenyl] -amide 5-cyano-furan-2-carboxylic acid 4- (4-methyl-piperazin-1 -yl) -2- (4-methyl-thiophen-3-yl) -phenyl] -amide salt of the trifluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1- (2-hydroxy-1-hydroxymethyl-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide . { 2-Cyclohex-1-enyl-4- [1 - (2-morpholin-4-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide Structure Name . { 2-cyclohex-1-enyl-4- [1- (3-morpholin-4-yl-propionyl) -piperidin-4-yl] -phenyl} 4-cyano-H-imidazole-2-carboxylic acid amide 5-Cyano-furan-2-carboxylic acid [2'-methyl-5- (4-methyl-piperazin-1-yl) -biphenyl-2-yl] -amide 5-cyano-furan-2-carboxylic acid [2'-fluoro-5- (4-methyl-piperazin-1-yl) -biphenyl-2-yl] -amide 5-cyano-furan-2-carboxylic acid [2-cyclohex-1-ene-4- (4-methyl-piperazin-1-yl) -phenyl] -amide Structure Name 5-cyano-furan-2-carboxylic acid 2- (3,6-dihydro-2H-pyran-4-yl) -4- (4-methyl-piperazin-1-yl) -phenyl-amide Trifluoroacetic acid salt of 4-cyano-1 H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide H Trifluoroacetic acid salt of 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide H 4-cyano-1 H-pyrrole-2-carboxylic acid [4- (1-acetyl-piperidin-4-yl) -2-cyclohex- -enyl-phenyl] -amide Structure Name [4- (1-Acetyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1 H -medazole-2-carboxylic acid Salt of trifluoroacetic acid [2- (4-methyl-cyclohex-1-yl) -4-piperidin-4-yl-phenyl] -amide of 4-cyano-1 H-imidazole-2-carboxylic acid Trifluoroacetic acid salt of 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl] -amide CF3C02H Structure Name . { 2-cyclohex-1-enyl-4- [1 - (2-methanesulfonyl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide Salt of trifluoroacetic acid [2-cyclohex-1-enyl-4- (1-pyridin-2-ylmethyl-piperidin-4-yl) -phenyl] -amide of 4-cyano-1 H-imidazole-2-acid carboxylic or Salt of trifluoroacetic acid [2- (4-methyl-cyclohex-1-enyl) -4- (1-pyridin-2-ylmethyl-piperidin-4-yl) -phenyl] -amide of 4-cyano-1 acid H-imidazole-2-J CF3C02H carboxylic N Structure Name salt of the trifluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1- (2-pyridin-2-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide salt of the trifluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1- (2-pyridin-3-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide salt of the trifluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1- (2-pyridin-4-yl-acetyl) -piperidin-4-yl] -phenyl} -4-cyano-1 H-imidazole-2-CF3C02H carboxylic acid amide Structure Name Trifluoroacetic acid salt of (2-cyclohex-1-enyl-4-. {1- [2- (1-methyl-1 H-imidazol-4-yl) -acetyl] -piperidin-4-yl}. 4-cyano-1 H imidazole-2-carboxylic acid phenyl) -amide salt of trifluoroacetic acid Ide la. { 2-cyclohex-1-enyl-4- [1 - (2-1 H-imidazol-4-yl-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide salt of the difluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1 (CF 3 CO 2 H) (2-morpholin-4-yl-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide Structure Name . { 2-Cyclohex-1-enyl-4- [1 - (2-methylamino-acetyl) -piperidin-4-b-yl] -phenyl} 4- cyano-1 H-imidazole-2-carboxylic acid amide (2-hydroxy-ethyl) -amide of 4-acid. { 4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenol} -piperidine-1-carboxylic acid 0 . { 2-Cyclohex-1-enyl-4- [1 - (2-methanesulfonyl-ethyl) -piperidin-4-yl] -phenyl} 4- cyano-1 H-imidazole-2-carboxylic acid amide . { 2-cyclohex-1-enyl-4- [1 - (1-oxy-pyridine-4-carbonyl) -piperidine-4-JL N-A-C 1-l] -phenyl} -amide of 4- cyano-1 H-imidazole-2-carboxylic acid 0 Structure Name 2-Cyclohex-1-enyl-4- [1 - (1-oxy-oyridin-3-carbonyl) -p- peridn-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide . { 2-cyclohex-1-enyl-4- [1- (pyridine-3-carbonyl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide OR Trifluoroacetic acid salt of (2-cyclohex-1-enyl-4- { 1 - [2- (2-hydroxy-ethylamino) -acetyl] - IH TS piperidin-4-yl.} - phenyl) - 4-cyano-1 H-imidazole-2-TFA / acid amide or carboxylic h H 0 Trifluoroacetic acid salt of (2-cyclohex-1-enyl-4-. {1- [2- (2-hydroxy-ethyl) -methyl-amino-acetyl] -piperidin-4-yl} -phenyl ) - 4-cyano-1 H-imidazole-2-carboxylic acid amide Structure Name salt of trifluoroacetic acid [4- (1-acetyl-piperidin-4-yl) -2- (1, 2,5,6-tetrahydro-pyridin-3-yl) -phenyl] -amide of 4-cyano- 1 H-imidazole-2-carboxylic acid (4. {4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl} -piperidine-1-trifluoroacetic acid salt il) -acetic salt of the trifluoroacetic acid of. { 4- [1 - (3-amino-3-methyl-butyryl) -piperidin-4-yl] -2-cyclohex-1-enyl-phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide 4H- [1, 2,4] -triazole-3-carboxylic acid bis-trifluoroacetic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide EXAMPLE 1 5-Cyano-furan-2-carboxylic acid To a flask with a stir bar and a Vigreaux column under Ar, 2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol), hydroxylamine hydrochloride (2.7 g, 40 mmol) and dry pyridine (50 mL) were added. ). The mixture was heated to 85 ° C, acetic anhydride (40 mL) was added and the mixture was stirred for 3 hours. After cooling to 60 ° C, water (250 mL) was added and the mixture was stirred at room temperature for 70 hours. Mix it was acidified to pH 2 with concentrated hydrochloric acid and extracted with 3: 1 dichloromethane-isopropanol (8 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a tan solid (1.26 g, 46%). . 1 H NMR (CD 3 OD, 400 MHz): d 14.05 (broad s, 1 H), 7.74 (d, 1 H, J = 3.8 Hz), 7.42 (d, 1 H, J = 3.8 Hz).

EXAMPLE 2 4-Cyano-1 H-pyrrole-2-carboxylic acid The title compound was prepared by the literature method (Loader and Anderson, Canadian J. Chem. 59: 2673 (1981)). 1 H NMR (CDCl 3, 400 MHz): d 12.70 (broad s, 1 H), 7.78 (s, 1 H), 7. 13 (s, 1 H).

EXAMPLE 3 Salt of potassium 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate a) 1- (2-Trimethylsilanyl-ethoxymethyl) -1 H-imidazole-4-carbonitrile SEM One flask loaded with imidazole-4-carbonitrile (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2- (trimethylsilyl) ethoxymethyl chloride (SEMCI) (0.95 mL, 5.3 mmol), K2C03 (1.40 g, 10.4 mmoles) and acetone (5 mL) was stirred for 10 hours at room temperature. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer was dried over MgSO4. The crude product was eluted from a 20 g SPE cartridge (silica) with 30% EtOAc / hexane to provide 0.80 g (70%) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m / z) calculated for C10H17N3OSi, 224.1 (M + H), found 224.1. b) 2-Bromo-1 - (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4- To a solution of 1- (2-trimethylsilanyl-ethoxymethyl) -1 / - / - imidazole-4-carbonitrile (0.70 g, 3.1 mmol) (as prepared in the previous step) in CCI4 (10 mL), was added NBS (0.61 g, 3.4 mmol) and AIBN (cat), and the mixture was heated at 60 ° C for 4 hours. The reaction was diluted with EtOAc (30 mL) and washed with NaHCC (2 x 30 mL) and brine (30 mL), and the organic layer was dried over Na 2 SO and then concentrated. The title compound was eluted from a 20 g SPE cartridge (silica) with 30% EtOAc / hexane to provide 0.73 g (77%) of a yellow solid. Mass spectrum (Cl (CH4), m / z) calculated for C10H16BrN3OSi, 302.0 / 304.0 (M + H), found 302.1 / 304.1. c) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -H-imidazole-2-carboxylic acid ethyl ester To a solution of 2-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1 / - / - imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at -40 ° C, a solution of i-PrMgCI 2M in THF (1 mL) was added dropwise. The reaction was allowed to stir for 10 minutes at -40 ° C and then cooled to -78 ° C, and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. The reaction was allowed to reach room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous NH 4 Cl, diluted with EtOAc (20 mL) and washed with brine (2 x 20 mL), and the organic layer was dried over Na 2 SO and then concentrated. The title compound was eluted from a 20 g SPE cartridge (silica) with 30% EtOAc / hexane to provide 0.4 g (74%) of a colorless oil. Mass spectrum (ESI, m / z): calculated for C 3H2i N303Si, 296.1 (M + H), found 296.1. d) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carboxylate potassium salt To a solution of 4-cyano-1- (2-trimethylsilane-ethoxymethyl) -1 / - / - imidazole-2-carboxylic acid ethyl ester (0.4 g, 1.3 mmol) (as prepared in step prep) in ethanol (3 mL), a 6M KOH solution (0.2 mL) was added, and the reaction was stirred for 10 minutes and then concentrated to provide 0.40 g (100%) of the title compound as a yellow solid. . 1 H NMR (400 MHz, CD 3 OD) d 7.98 (s, 1 H), 5.92 (s, 2 H), 3.62 (m, 2 H), 0.94 (m, 2 H), 0.00 (s, 9 H). Mass spectrum (ESl-neg, m / z) calculated for CnH17N303Si, 266.1 (M-H), found 266.0.

EXAMPLE 4 f4- (4-Methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-in-phenin-amide of 5- cyano-furan-2-carboxylic acid a) 1 - (3-Bromo-4-nitro-phenyl) -4-methyl-piperazine 2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in two portions to pure N-methylpiperazine (8 mL) at 0 ° C and allowed to warm to room temperature. The reaction was heated at 60 ° C for 1 hour and then diluted with 50 mL of EtOAc and poured into H20 (50 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated in vacuo to give 580 mg (45%) of the title compound as a yellow solid: Mass spectrum (ESI, m / z): calculated for C1 i H i4BrN3O2, 300.0 (M + H), found 300.1. b) 4,4,5,5-Tetramethyl-2- (3-methyl-thiophen-2-yl) - [1, 3,2ldioxaborolane To a stirred solution of 2-bromo-3-methylthiophene (337 mg, 1.9 mmol) in 8 mL of THF at -40 ° C, n-BuLi (0.8 mL, 2.5 M / hexanes) was added thereto, and the reaction was allowed to stir for 30 minutes. At this time, 2-isopropoxy-4,4,5,5-tetramethyl- [1,2,2] dioxaborolane (775 μ? _, 3.8 mmol) was added and the reaction allowed to warm to room temperature and stirring continued for 1 hour. The reaction was then cooled to 0 ° C and quenched with saturated aqueous NaHCO3 (10 mL). The mixture was poured into EtOAc (100 mL), washed with H2O (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography on silica gel (20% EtOAc-hexanes) gave 224 mg (53%) of the title compound as an oil.

H NMR (CDCl 3, 400 MHz): d 1.36 (s, 12 H), 2.5 (s, 3 H), 6.99 (d, 1 H, J = 4.8 Hz), 7.50 (d, 1 H, J = 4.8 Hz ). c) 1 -Methyl-4- [3- (3-methyl-thiophen-2-yl) -4-nitro-phenin-piperazine To a flask containing 1- (3-bromo-4-nitro-phenyl) -4-methyl-piperazine (68 mg, 0.2 mmol, as prepared in Example 4, step (a)), 4.4.5 , 5-tetramethyl-2- (3-methyl-thiophen-2-yl) - [1,2] dioxaborolane (61 mg, 0.27 mmol, as prepared in the previous step) and Pd (PPh3) 4 (14 mg, 6 mol%), toluene (3 ml_), ethanol (3 ml_) and 2M Na 2 CO 3 (4 ml_) were charged. The resulting mixture was heated at 80 ° C for 2 hours and then poured into EtOAc (25 ml_). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography on silica gel (EtOAc) gave 40 mg (63%) of the title compound as a light yellow solid. Mass spectrum (ESI, m / z): calculated for C 16 H 19 N 3 O 2 S, 318.1 (M + H), found 318.2. d) [4- (4-methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-yl) -phenyl-1-amide of 5-cyano-furan-2-carboxylic acid The 1-methyl-4- [3- (3-methyl-thiophen-2-yl) -4-nitro-phenyl] -piperazine (60 mg, 0.18 mmol, as prepared in the previous step), was stirred at 40.degree. mg of 5% Pd-C in MeOH (5 mL) under H2 (1 atmosphere) for 2 hours. The reaction was filtered through Celite and concentrated in vacuo to provide 40 mg (72%) of 4- (4-methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-yl) phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4- (4-methyl-piperazin-1-yl) -2- (3-methyl-thiophen-2-yl) -phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)), in the presence of DIEA (61 pL, 0.34 mmol), provide 18.9 mg (36%) of the title compound as a yellow solid. 1 H NMR (CDCl 3, 400 MHz): d 2.13 (s, 3 H), 2.38 (s, 3 H), 2.59-2.62 (m, 4 H), 3.24-3.27 (m, 4 H), 6.92 (d, 1 H, J = 2.8 Hz), 7.06 (d, 1 H, J = 5.1 Hz), 7.15 (d, 1 H, J = 3.7 Hz), 7.19 (d, 1 H, J = 3.7 Hz), 7.02 (dd, 1 H) , J = 2.8, 9.0 Hz), 7.42 (d, 1 H, J = 5.1 Hz), 8.1 1 (s, 1 H), 8.34 (d, 1 H, J = 9.0 Hz); Mass spectrum (ESI, m / z): calculated for C22H22 4O2S, 407.1 (M + H), found 407.1.

EXAMPLE 5 r4- (4-Methyl-piperazin-1-yl) -2- (4-methyl-thiophen-3-yl) -phenyl-amide of 5- cyano-furan-2-carboxylic acid a) 4.4.5.5-Tetramethyl-2- (2-methy1-thiophen-3-yl) - [1, 3,21-dioxaborlane Using a procedure similar to Example 4, step (b), 3-bromo-4-methylthiophene (571 mg, 3.2 mmol) was treated with n-BuLi (1.41 mL, 2.5M / hexanes), and then left react with 2-isopropoxy-4,5,5,5-tetramethyl- [1,2] dioxaborolane (775 pl_, 3.8 mmol) to give 189 mg (26%) of the title compound as a colorless oil. 1 H NMR (CDCl 3, 400 MHz): d 1.32 (s, 12 H), 2.42 (s, 3 H), 6.90-6.91 (m, 1 H), 7.84 (d, 1 H, J = 2.9 Hz). 1-Methyl-4- [3- (4-methyl-thiophen-3-yl) -4-nitro-phenyl-piperazine Using a procedure similar to Example 4, step (c), 1- (3-bromo-4-nitro-phenyl) -4-methyl-piperazine (162 mg, 0.54 mmol), 4,4,5,5-tetramethyl- 2- (2-methyl-thiophen-3-yl) - [1,2,2] dioxaborlane (145 mg, 0.64 mmol) and Pd (PPh 3) 4 (37 mg, 6% in mol) were allowed to react to provide 108 mg (71%) of the title compound as a yellow solid. 1 H NMR (CDCl 3, 400 MHz): d 2.02 (s, 3 H), 2.37 (s, 3 H), 2.55-2.57 (m, 4 H), 3.42-3.45 (m, 4 H), 6.66 (d, 1 H, J = 2.8 Hz), 6.87 (s, 1 H), 6.99-7.00 (m, 1 H), 7.09 (d, 1 H, J = 3.2 Hz), 8.13 (d, 1 H, J = 9.2 Hz). c) 4- (4-Methyl-piperazin-1-yl) -2- (4-methyl-thiophen-3-yl) -phenylamine Using a procedure similar to Example 4, step (d), 1-methyl-4- [3- (4-methyl-thiophen-3-yl) -4-nitro-phenyl] -piperazine (100 mg, 0.32 mmol) was stirred with 80 mg of 5% Pd-C under H2 to give 82 mg (89%) of the title compound as a dark oil, which was used immediately without further purification, spectrum (ESI, m / z): calculated for Ci6H2i N3S, 288.15 (M + H), found 288.1. d) [4- (4-methyl-piperazin-1-yl) -2- (4-methyl-thiophen-3-yl) -phenyl-amide of 5-cyano-furan-2-carboxylic acid Using a procedure similar to Example 9, step (c), the 5-cyano-furan-2-carbonyl chloride (64 mg, 0.41 mmol, as prepared in Example 9, step (c)), was allowed to react with 4- (4-methyl-piperazin-1-yl) -2- (4-methyl-thiophen-3-yl) -phenylamine (80 mg, 0.27 mmol, as prepared in the previous step), in the presence of DIEA (0.10 mL, 0.59 mmol), to provide 25.8 mg (24%) of the title compound as a yellow solid. 1 H NMR (CDCl 3, 400 MHz): d 2.09 (s, 3 H), 2.37 (s, 3 H), 2.59-2.60 (m, 4 H), 3.24-3.26 (m, 4 H), 6.83 (d, 1 H, J = 2.9 Hz), 6.98-7.06 (m, 2H), 7. 14-7.21 (m, 3H), 7.96 (s, 1 H), 8.32 (d, 1 H, J = 9.0 Hz). Mass spectrum (ESI, m / z): calculated for C22H22N402S, 407.1 (M + H), found 407.1.

EXAMPLE 6 Salt of trifluoroacetic acid of 4- (2-cyclohex-1-enyl-4-f1 - (2-hydroxy-1-hydroxymethyl-ethyl) -piperidin-4-yl-phenyl) -amide of 4-acid cyano-1 H- imidazole-2-carboxylic acid a) (4-cyano-1 H 2-cyclohex-1-enyl-4-ri- (2,2-dimethyl-f 1 .31dioxan-5-D-piperidin-4-yl-1-phenyl) -amide) -imidazole-2-carboxylic acid To a suspension of the trifluoroacetic acid salt of 4-cyano-1 H-imidazole-2 (cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide carboxylic acid (81 mg, 0.16 mmol, as prepared in Example 14, step (b)) in CH 2 Cl 2 (3 ml), was added NEt 3 (33 pL, 0.24 mmol) The solution was then treated with 2, 2-dimethyl- [1, 3] dioxan-5-one (31 mg, 0.24 mmol) and the reaction was allowed to stir for 3 h At this time, NaBH (OAc) 3 (51 mg, 0.24 mmol) was added in a portion, and the reaction was left Stir for an additional 4 hours. The reaction was diluted with H2O (10 mL_) and extracted with EtOAc (2 x 25 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography on silica gel (10% MeOH-CHCl3), gave 22 mg (28%) of the title compound as a white matte semi-solid. Mass spectrum (ESI, m / z): calculated for C28H35N5O3, 490.2 (M + H), found 490.6. b) Trifluoroacetic acid of the 4-cyano- (2-cyclohex-1-enyl-4- [1- (2-hydroxy-1-hydroxymethyl-ethyl) -piperidin-4-yl-phenyl) -amide 1 H-imidazole-2-carboxylic acid To a solution of the. { 2-Cyclohex-1-enyl-4- [1- (2,2-dimethyl- [1,3] dioxan-5-yl) -piperidin-4-yl] -phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide (22 mg, 0.04 mmol, as prepared in the previous step) in THF-H20 (1 mL, 4: 1 volume / volume), was added TFA (0.4 mL) and the reaction was allowed to stir for 1 hour. Removal of the solvent in vacuo afforded 14 mg (60%) of the title compound as an amber foam. 1 H NMR (CD 3 OD, 400 MHz): d 1.78-1.90 (m, 4 H), 2.03-2.16 (m, 3 H), 2.29 (broad s, 4 H), 2.88-2.96 (m, 1 H), 3.37- 3.40 (m, 1 H), 3.46-3.53 (m, 2H), 3.74-3.78 (m, 3H), 5.83 (s, 1 H), 7.13 (d, 1 H, J = 2.0 Hz), 7.22 (dd) , 1 H, J = 2.0, 8.4 Hz), 8.03 (s, 1 H), 8.17 (d, 1 H, J = 8.4 Hz); Mass spectrum (ESI, m / z): calculated for C25H31N503, 450.2 (M + H), found 450.2.

EXAMPLE 7 { 4-cyano-1H-imidazole-2-carboxylic acid 2-cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-acetyl) -piperidin-4-yl-1-phenyl] -amide To a solution of the morpholin-4-yl-acetic acid ethyl ester (17 mg, 0.67 mmol) in ethanol (4 mL), 6N KOH (10 pL, 0.67 mmol) was added via syringe and the stirring continued. during 3 hours. Concentration in vacuo afforded 122 mg (100%) of the potassium salt of morpholin-4-yl-acetic acid. To a mixture of the potassium salt of morpholin-4-yl-acetic acid (29 mg, 0.15 mmol), of the trifluoroacetic acid salt of (2-cyclohex-1-enyl-4-piperidin-4-yl) phenyl) -amide of 4-cyano-1 H-imidazole-2-carboxylic acid (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH 2 Cl 2 ( 4 mL), DIEA (51 pL, 0.29 mmol) was added, and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2 x 25 mL), dried (Na2SO4) and concentrated in vacuo. The purification of the crude product by preparative TLC on silica gel afforded 8.1 mg (12%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35. -3.40 (m, 1 H), 3.72 (broad s, 4H), 4.16-4.22 (m, 1 H), 4.73-4.77 (m, 1 H), 5.82 (s, 1 H), 7.00 (s, 1 H), 7.12 (dd, 1 H, J = 0.6, 8.0 Hz), 7.73 (s, 1 H), 8.27 (d, 1 H, J = 8.1 Hz), 9.48 (s, 1 H); Mass spectrum (ESI, m / z): calculated for C28H34N6O3, 503.27 (M + H), found 503.1.

EXAMPLE 8 (2-Cyclohex-1 ^ ni -ri- (3-morpholin ^ -yl-propionyl) -piperidin-4-in-phenyl} - 4-cyano-1H-imidazole-2-carboxylic acid amide To a flask containing the potassium salt of 3-morpholin-4-yl-propionic acid (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, the trifluoroacetic acid salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (179 mg, 0.36 mmol) , as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol) and HOBT (68 mg, 0.5 mmol), DMF (4 mL) was added. To the stirred suspension was added DIEA (157 pL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by preparative TLC on silica gel to provide 10.4 mg (6%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (broad s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (broad s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81 -5.82 (m, 1 H), 6.81 -6.82 (m, 1 H), 6.99-7.00 (m, 1 H), 7.09-7.1 3 (m, 1 H), 7.70 (s, 1 H), 8.26 (d, 1 H, J = 8.2 Hz), 9.51 (s, 1 H); Mass spectrum (ESI, m / z): calculated for C29H36N6O3, 517.28 M + H), found 517.3.

EXAMPLE 9 5-Cyano-furan-2-carboxylic acid 5-cyano-furan-2-carboxylic acid 5-cyano-furan-2-methyl-5- (4-methyl-piperazin-1-yl) -biphenyl-2-in-amide a) 1 - (3-Bromo-4-nitro-phenyl) -4-methyl-piperazine To a cooled (0 ° C) solution of 1.00 g (4.55 mmol) of 2-bromo-4-fluoronitrobenzene (Oakwood) in 12 mL of EtOH, 1.52 mL (13.7 mmol) of piperidine was added. The solution was stirred at 0 ° C for 0.5 hours, and then at 60 ° C for 4 hours. The mixture was concentrated in vacuo, dissolved in EtOAc (60 mL), washed with water (3 x 100 mL) and brine (100 mL), and dried (Na2SO4). Concentration in vacuo and chromatography on an SPE column on 50 g silica with 1 -3% MeOH-dichloromethane gave 1.06 g (77%) of the title compound as a yellow brown solid. Mass spectrum (ESI, m / z): calculated for C HuBrNaOz, 300.0 (M + H, 79Br), found 300.1. b) 1-Methyl-4- (2'-methyl-6-nitro-biphenyl-3-yl) -piperazine A mixture of 200 mg (0.666 mmoles) of 1- (3-bromo-4-nitro-phenyl) -4-methyl-piperazine (as prepared in the previous step), 136 mg (0.999 mmole) and 77.0 mg (0.0666) mmoles) of tetracyc (triphenylphosphine) palladium (0) under Ar, was added to 4.0 mL of degassed dimethoxyethane (DME) and 400 μl (0.799 mmol) of 2.0 M aqueous Na 2 CO 3. The mixture was heated with stirring under Ar at 80 ° C for 14 hours. The cooled mixture (room temperature) was concentrated and chromatographed on a SPE column on 10 g silica with 1-5% MeOH in dichloromethane-hexane (1: 1). The product fractions were treated with 80 mg of decolorizing carbon, filtered, concentrated and then rechromatographed on a similar column with 1-3% EtOH-dichloromethane to provide 265 mg of the title compound as a resin. yellow (75% pure by H NMR as a mixture with triphenylphosphine), which was used in the next reaction without further purification: Mass spectrum (ESI, m / z): calculated for 312. 2 (M + H), found 312.2. c) 5-cyano-furan-2-carboxylic acid f2'-methyl-5- (4-methyl-piperazin-1-yl) -biphenyl-2-yl-1-amide A mixture of 140 mg (0.337 mmol based on a 75% purity) of 1-methyl-4- (2'-methyl-6-nitro-biphenyl-3-yl) -piperazine (as prepared in the previous step) ) and 70 mg of 10% palladium on carbon (Degussa type E 01 -NE / W, Aldrich, 50% by weight of water) in 5 mL of THF, was stirred vigorously under a hydrogen balloon for 1 hour. The mixture was filtered (Celite), washed with dichloromethane (2 x 2 mL) and the resulting aniline solution was placed under Ar and used immediately in the next reaction. Simultaneously to the above reduction, 55.4 mg (0.404 mmoles) of the 5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL of anhydrous dichloromethane under a CaSO4l drying tube was treated with 52.9 pL ( 0.606 mmoles) of oxalyl chloride followed by 10 pL of anhydrous DMF. The solution was stirred for 25 minutes and concentrated rapidly in vacuo at 20-25 ° C. The resulting 5-cyano-furan-2-carbonyl chloride was placed under high vacuum for 2-3 minutes and then placed immediately under Ar, cooled to 0 ° C in an ice bath and treated with the aniline solution produced above, followed by 141 pL (0.808 mmoles) of A /, A / -diisopropylethylamine (DIEA). After stirring for 30 minutes at room temperature, the mixture was concentrated in vacuo and the resulting residue was chromatographed on a SPE column on 20 g silica with 2-10% EtOH-dichloromethane, to give a yellow resin ( which was crystallized from EtOAc-hexane), to give 17.2 mg (13%) of the pure title compound as a yellow solid together with 70.3 mg of the impure title compound. The impure fraction was dissolved in 50 mL of EtOAc, washed with saturated aqueous NaHCO3-1 M K2C03 (1: 1, 2 x 20 mL) and brine (20 mL), dried (Na2SO4) and concentrated to provide 43.4 mg (32%) additional title compound as a crystalline yellow solid (total yield 45%). 1 H NMR (CDCl 3, 400 MHz): d 8.32 (d, 1 H, J = 9.0 Hz), 7.73 (broad s, 1 H), 7.34-7.54 (m, 3 H), 7.25 (d, 1 H, J = 7.7 Hz), 7.12, 7.14 (AB c, 2H, J = 3.7 Hz), 7.01 (dd, 1 H, J = 9.0, 2.8 Hz), 3.25-3.27 (m, 4H), 2.59-2.62 (m, 4H ), 2.38 (s, 3H) and 2.15 (s, 3H). Mass spectrum (ESI, m / z): calculated for C2iH24N403, 401.2 (M + H), found 401.1.

EXAMPLE 10 5-Cyano-furan-2-carboxylic acid r2'-fluoro-5- (4-methyl-piperazin-1-yl) -biphenyl-2-n-amide a) 1 - (2'-Fluoro-6-nitro-biphenyl-3-yl) -4-methyl-piperazine The procedure of Example 9, step (b) was continued using 75.0 mg (0.250 mmol) of 1- (3-bromo-4-nitro-phenyl) -4-methyl-piperazine (as prepared in Example 9, step (a)), 136 mg (0.999 mmoles) of 2-fluorophenylboronic acid, 26.8 mg (0.0232 mmoles) of tetracis (triphenylphosphine) palladium (0) and 400 pL (0.799 mmoles) of 2.0 M aqueous Na2C03 in DME, except that the mixture was heated for 22 hours. Chromatography on an SPE column on 5 g silica with 1-5% MeOH in dichloromethane-hexane (1: 1) afforded 95.0 mg of the title compound (76% purity by 1 H NMR as a mixture with triphenylphosphine) as a yellow resin that used in the next reaction without further purification. Mass spectrum (ESI, m / z): calculated for C ^ H ^ F ^ Oa, 316.1 (M + H), found 316.2. b) 5-cyano-furan-2-carboxylic acid [2-fluoro-5- (4-methyl-piperazin-1-yl) -biphenyl-2-in-amide The procedure of Example 9, step (c) was continued using 93.2 mg (0.225 mmoles based on a purity of 76%) of the 1- (2"-fluoro-6-nitro-biphenyl-3-yl) -4-methyl piperazine (as prepared in the previous step), 46 mg of 10% palladium on carbon, 37.0 mg (0.270 mmoles) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 35.3 pl_ ( 0.405 mmoles) of oxalyl chloride, 5.0 pL of anhydrous DMF and 94.1 pL (0.540 mmoles) of DIEA Chromatography on an SPE column on 5 g silica with 1-4% MeOH-dichloromethane gave 69.8 mg (77%) ) of the title compound as a yellow resin: 1 H NMR (CDCl 3, 400 MHz): d 8.04 (d, 1 H, J = 9.0 Hz), 7.93 (broad s, 1 H), 7.434-7.48 (m, 1 H ), 7.37 (td, 1 H, J = 7.5, 1.8 Hz), 7.22-7.31 (m, 2H), 7.13, 7.18 (AB c, 2H, J = 3.7 Hz), 7.02 (dd, 1 H, J = 9.0, 2.9 Hz), 6.88 (d, 1 H, J = 2.9 Hz), 3.24-3.27 (m, 4H), 2.57-2.60 (m, 4H) and 2.36 (s, 3H). mass (ESI, miz): calculated for C23H21 FN4O2, 405.2 (M + H), found 405.2.

EXAMPLE 11 5-Cyano-furan-2-carboxylic acid f2-cyclohex-1-enyl-4- (4-methyl-piperazin-1-yl) -phenyl-amide a) 1- (3-Cyclohex-1-enyl-4-nitro-phenyl) -4-methyl-piperazine A mixture of 102 mg (0.340 mmol) of the 1- (3-bromo-4-nitro-phenyl) -4-methyl-piperazine (as prepared in Example 9, step (a)), 59.7 mg ( 0.474 mmoles) of cyclohexen-1-boronic acid, 43.8 mg (0.0379 mmoles) of tetracis (tripanephosphines) palladium (0) under Ar was treated with 206 pL (0.412 mmoles) of 2.0 M degassed aqueous Na2CO3, 0.6 ml_ of anhydrous toluene degassed and 0.2 mL dehydrated anhydrous EtOH and the mixture was heated at 100 ° C for 21 hours. After cooling to room temperature, the mixture was poured into EtOAc (10 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Chromatography on an SPE column on 5 g silica with 1-3% EtOH in dichloromethane gave 126 mg of the title compound (74% purity by RP-HPLC (column C18) as a mixture with triphenylphosphine) as an oil yellow which was used in the next reaction without further purification. Mass spectrum (ESI, m / z): calculated for C17H23N3O3, 302.2 (M + H), found 302.2. b) [2-cyclohex-1-enyl-4- (4-methyl-piperazin-1-yl) -phenyl-amide of 5-cyano-fura? -2-carboxylic acid At 122 mg (0.299 mmol based on a purity of 74%) of 1- (3-cyclohex-1-enyl-4-nitro-phenyl) -4-methyl-piperazine (as prepared in the previous step) in 5.0 mL of EtOH-water (2: 1), 83.8 mg (1.50 mmoles) of iron powder and 160 mg (2.99 mmoles) of NH4CI were added thereto, and the mixture was refluxed under Ar for 12 hours. 83.8 mg (1.50 mg) were added additional mmoles) of iron powder, and the mixture was refluxed for 1 hour. The mixture was poured into EtOAc (12 mL), filtered (Celite), washed with EtOAc (2 x 4 mL), concentrated in vacuo and dissolved in anhydrous THF (4.0 mL). The resulting aniline solution was placed under Ar and used immediately in the next reaction. 61.6 mg (0.449 mmoles) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL of anhydrous dichloromethane under a CaSO4 drying tube, treated with 60.0 pL (0.688 mmoles) of oxalyl chloride followed by 10 pL of anhydrous DMF. The solution was stirred for 25 minutes and concentrated rapidly in vacuo at 20-25 ° C. The residue was placed under high vacuum for 2-3 minutes and then immediately placed under Ar, cooled to 0 ° C in an ice bath and treated with the aniline solution produced above, followed by 104 pL (0.598 mmol) of DIEA. After stirring 30 minutes at room temperature, the mixture was concentrated in vacuo, dissolved in EtOAc (20 mL), washed with 1 M K2CO3 (2 x 10 mL) and brine (10 mL), dried (Na2SO) and it was concentrated in vacuo. The resulting residue was chromatographed on an SPE column on 10 g silica with 1-4% MeOH-dichloromethane to give a yellow resin, which was then crystallized from Et 2 O-hexane to provide 84.7 mg (72%) ) of the title compound as a crystalline yellow solid. 1 H NMR (CDCl 3; 400 MHz): d 8.57 (s broad, 1 H), 8.26 (d, 1 H, J = 9.0 Hz), 7.20, 7.23 (AB c, 2 H, J = 3.7 Hz), 6.86 (dd, 1 H, J = 9.0, 2.9 Hz), 6. 74 (d, 1 H, J = 2.9 Hz), 5.84-5.85 (m, 1 H), 3.20-3.22 (m, 4H), 2.57-2.59 (m, 4H), 2.36 (s, 3H), 2.23- 2.30 (m, 4H) and 1.79-1.84 (m, 4H). Mass spectrum (ESI, m / z): calculated for C23H26N4O2, 391.2 (M + H), found 391.2.

EXAMPLE 12 f2- (3,6-Dihydro-2H-pyran-4-yl) -4- (4-methyl-piperac-n-1-yl) -phenyl-amide of 5-cyano-furan-2-carboxylic acid a) 1 -f3- (3,6-Dihydro-2H-pyran-4-yl) -4-nitro-phenin-4-methyl-piperazine 1- (3-Bromo-4-nitro-phenyl) -4-methyl-piperazine (as prepared in Example 9, step (a)) (225.1 mg, 0.79 mmol), K2C03 (310.9 mg, 2.25 mmoles) and 4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyran (Murata, M., et al, Synthesis, 778, (2000)) (157 mg, 0.75 mmol) in dioxane (5 ml_) was heated at 80 ° C overnight under Ar. The reaction mixture was allowed to cool to room temperature, concentrated and the resulting residue was chromatographed on silica (10% EtOAc / hexane-20% MeOH / EtOAc) to obtain the title compound (82 mg, 36% ). 1 H NMR (CDCl 3, 400 MHz): d 8.04 (d, 1 H, J = 9.4 Hz), 6.78 (dd, 1 H, J = 9.4, 2.6 Hz), 6.58 (m, 1 H, J = 2.6 Hz) , 5.58 (m, 1 H), 4.34 (m, 2H), 3.95 (t, 2H, J = 5.3 Hz), 3.46 (m, 4H), 2.57 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H). b) f2- (3,6-Dihydro-2H-pyran-4-yl) -4- (4-methyl-piperazin-1-yl) -phenyl-amide of 5-cyano-furan-2-carboxylic acid 1- [3- (3,6-Dihydro-2H-pyran-4-yl) -4-nitro-phenyl] -4-methyl-piperazine (as prepared in the previous step) (80 mg, 0.26 mmol) was converted to the corresponding amine using a procedure similar to Example 4, step (d) and coupling with 5-cyano-furan-2-carbonyl chloride as prepared in Example 9, step (c) (obtained from 137 mg, 1.00 mmol of acid 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH 2 Cl 2 (2 mL) at 0 ° C. The product was isolated by flash chromatography on silica (50% EtOAc / hexane-10% MeOH / EtOAc) to obtain the title compound (62.2 mg, 60%). H NMR (CDCl 3, 400 MHz): d 8.35 (broad s, 1 H), 8.12 (d, 1 H each, J = 8.76 Hz), 7.24 (d, 1 H, J = 5.08 Hz), 7.19 (d , 1 H, J = 5.08 Hz), 6.88 (dd, 1 H, J = 8.76, 2.7 Hz), 6.73 (d, 1 H, J = 2.7 Hz), 5.88 (broad s, 1 H), 4.34 (m , 2H), 3.94 (t, 2H, J = 5.3 Hz), 3.23 (m, 4H), 2.59 (m, 4H), 2.38 (broad s, 5H). LC-MS (ESI, m / z): calculated for C22H24N403, 393.1 (M + H), found 393.2.

EXAMPLE 13 Salt of trifluoroacetic acid from (2-cyclohex-1-enyl-4-piperidin-4-yl-phenylethyl-4-cyano-1H-pyrrole-2-carboxylic acid 4- (4-Amino-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester The title compound was prepared by Suzuki coupling of the 4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -phenylamine with the ter-butyl ester of the 4- trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid (Synthesis, 993, (1991)) according to the procedure in Example 35, step (b). Mass spectrum (ESI, m / z): calculated for Ci6H22N202, 275.2 (M + H), found 275.1. 4- (4-Amino-phenyl) -piperidine-1-carboxylic acid tert-butyl ester A solution of the 4- (4-amino-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert -butyl ester (0.35 g, 1.2 mmol) (as prepared in the previous step) in methanol , was subjected to hydrogenation during 10% Pd / C at 1,406 kgf / cm2 (20 psi) for 1 hour. The solution was filtered and concentrated to give 0.35 g (100%) of the title compound as a yellow solid: Mass spectrum (ESI, m / z): calculated for Ci6H24N202, 277.2 (M + H), found 277.1. c) 4- (4-Amino-3-bromo-phenyl) -piperidin-1-carboxylic acid tert-butyl ester To a solution of 4- (4-amino-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step) in DCM (3 mL), added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol) and the reaction was stirred at room temperature for 10 hours. The reaction was diluted with EtOAc (10 mL) and washed with NaHCO 3 (2 x 10 mL) and brine (10 mL). Concentration of the organic layer gave 0.26 g (100%) of the title compound as a yellow foam. Spectrum of masses (ESI, miz): calculated for Ci6H23BrN202, 355.1 (M + H), found 355.1. d) 4- (4-Amino-3-cyclohex-1-enyl-phenyl) -piperidin-1-carboxylic acid tert-butyl ester A flask was charged with the 4- (4-amino-3-bromo-phenyl) -piperidin-1-carboxylic acid tert-butyl ester (0.13 g, 0.36 mmol) (as prepared in the previous step), cyclohex acid -1-enyl boronic acid (0.060 g, 0.48 mmol), Pd (PPh3) 4 (0.04 g, 10 mol%), aqueous Na2CO3 2M (1.5 mL), ethanol (1.5 mL) and toluene (3 mL) and heated at 80 ° C for 3 hours. The reaction was diluted with EtOAc (10 mL), washed with NaHCO3 (2 x 10 mL) and brine (10 mL) and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20 g SPE cartridge (silica) with 30% EtOAc / hexane to provide 0.10 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, m / z): calculated for C22H32N2O2, 357.2 (M + H), found 357.1. e) Salt of trifluoroacetic acid of 4-cyano-1 H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide. A flask was charged with ester ter. 4- (4-amino-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid bismic (0.050 g, 0.14 mmol) (as prepared in the previous step), 4-cyano acid -1 H-pyrrole-2-carboxylic acid (0.019 g, 0.14 mmole) (as prepared in Example 2), EDCI (0.040 g, 0.21 mmole), HOBt (0.019 g, 0.14 mmole), DIEA (0.073 ml_, 0.42 mmoles), and DCM (0.5 mL) and stirred at 25 ° C for 10 hours. The reaction was loaded directly into a 10 g solid phase extraction cartridge (SPE) (silica), and the resulting intermediate was eluted with 30% EtOAc / hexane. This compound was stirred at room temperature for 1 hour in 50% TFA / DCM (2 mL) and then concentrated and purified by RP-HPLC (C18), eluted with 30-50% CH3CN in 0.1% TFA H20 for 12 minutes to provide the title compound (0.052 g, 77%). 1 H NMR (400 MHz, CD 3 OD): d 7.59 (s, 1 H), 7.50 (d, 1 H), 7.22 (d, 1 H), 7.16 (m, 2H), 5.74 (m, 1 H), 3.54 (m, 2H), 3.16 (m, 2H), 2.94 (m, 1 H), 2.29 (m, 2H), 2.15 ( m, 4H), 1.92 (m, 2H), 1.72 (m, 4H). Mass spectrum (ESI, miz): calculated for C23H26N4O, 375.2 (M + H), found 375.1.

EXAMPLE 14 Salt of the trifluoroacetic acid of the 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenylamino-acid a) 4- (4- { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonin-amino) -3-cyclohex-1-tert-butyl ester -enyl-phenyl) -peridin-1-carboxylic acid To a solution of the salt of potassium 4-cyano-1- (2-trimethylsilyl-ethoxymethyl) -1 H-imidazole-2-carboxylate (3.34 g, 10.9 mmol) (as prepared in Example 3, step (d) )) DIEA was added in 20 mL of DCM (3.8 mL, 21.8 mmoles) and PyBroP (5.6 g, 12.0 mmol) and the reaction was stirred at 25 ° C for 15 minutes. A solution of the 4- (4-amino-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.9 mmol) (as prepared in Example 13, step ( d)) in 10 mL of DCM was added and the reaction was stirred for 8 hours at 25 ° C. The reaction was diluted with EtOAc (60 mL) and washed with NaHCO 3 (2 x 60 mL) and brine (100 mL), and the organic layer was dried over Na 2 SO 4 and then concentrated. The title compound was purified by flash chromatography (silica gel, 2% EtOAc / DCM) to provide 5.5 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, miz): calculated for C33H47N504Si, 606.2 (M + H), found 606.2. b) Exit of trifluoroacetic acid from 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide To a solution of the ester ter 4- (4- { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino acid} butyl. -3-cyclohex-1-enyl- phenyl) -piperidine-1-carboxylic acid (1.5 g, 2.5 mmol) (as prepared in the previous step) in 10 mL of DCM and 0.3 mL of EtOH was added 3 mL of TFA and the solution was stirred for 3 hours. hours at 25 ° C. The reaction was diluted with 5 mL of EtOH and then concentrated. The residue was crystallized from methanol and ethyl ether to give 0.85 g (70%) of the title compound as a white solid. 1 H NMR (400 MHz, CD 3 OD) d 8.18 (d, 1 H), 8.04 (s, 1 H), 7.22 (dd, 1 H), 7.12 (d, 1 H), 5.76 (m, 1 H), 3.54 (m, 2H), 3.16 (m, 2H), 2.92 (m, 1 H), 2.30 (m, 4H), 2.10 (m, 2H), 1.75 (m, 6H). Mass spectrum (ESI, m / z): calculated for C22H25N5O, 376.2 (M + H), found 376.2.

EXAMPLE 15 [4- (1-Acetyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenol-amide of 4-cyano-1 H-pyrrole-2-carboxylic acid The title compound was prepared from the trifluoroacetic acid salt of 4- cyano-1 H -pyrrole-2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl-amide acid. carboxylic acid (as prepared in Example 13, step (e)) according to the procedure in Example 37. 1 H NMR (400 MHz, CDCl 3) d 10.82 (s, 1 H), 8.28 (d, 1 H), 8.18 (s, 1 H), 7.48 (d, 1 H), 7.16 (dd, 1 H), 7.02 (s, 1 H), 6.72 (s, 1 H), 5.88 (m, 1 H), 4.82 ( m, 1 H), 3.98. (m, 1 H), 3.20 (m, 1 H), 2.70 (m, 2H), 2.29 (m, 4H), 2.18 (s, 3H), 1. 80 (m, 8H). Mass spectrum (ESI, m / z): calculated for C25H28N4O2, 417.2 (M + H), found 417.1.

EXAMPLE 16 4-cyano-1 H-imidazole-2-carboxylic acid f4- (1-acetyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide The title compound was prepared from the trifluoroacetic acid salt of 4-cyano-1 H-imidazole-2- (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide. carboxylic acid (as prepared in Example 13, step (b)) according to the procedure in Example 37: 1 H NMR (400 MHz, CDCl 3) d 13.12 (broad s, 1 H), 9.58 (s, 1 H) , 8.34 (d, 1 H), 7.76 (s, 1 H), 7.21 (dd, 1 H), 7.05 (d, 1 H), 5.86 (s, 1 H), 4.84 (m, 2 H), 4.00 ( m, 1 H), 3.22 (m, 1 H), 2.72 (m, 2H), 2.30 (m, 4H), 2.21 (s, 3H), 1.80 (m, 8H). Mass spectrum (ESI, m / z): calculated for C24H27N502, 418.2 (M + H), found 418.1.

EXAMPLE 17 Sai of 4-cyano-1H-imidazole-2-carboxylic acid trifluoroacetic acid f2- (4-methyl-cyclohex-1-enyl) -4-p -peridin-butyl-phenyl] -amide The title compound was prepared from the salt of potassium 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in Example 3, step (d)) and 4- [4-amino-3- (4-methyl-cyclohex-1-enyl) -phenyl] -piperidine-1-carboxylic acid tert-butyl ester (prepared according to the procedure in Example 13, step ( d), substituting 4-methyl-1-cyclohex-1-enyl boronic acid for cyclohex-1-enyl boronic acid) according to the procedure for Example 14: 1 H NMR (400 MHz, CD 3 OD): d 8.18 ( d, 1 H), 8.04 (s, 1 H), 7.22 (dd, 1 H), 7.12 (d, 1 H), 5.80 (m, 1 H), 3.54 (m, 2 H), 3.18 (m, 2 H) ), 2.94 (m, 1 H), 2.30 (m, 3H), 2.12 (m, 2H), 1.92 (m, 5H), 1.54 (m, 1 H), 1 .12 (d, 3H). Mass spectrum (ESI, m / z): calculated for C23H27N5O, 390.2 (M + H), found 390.2.

EXAMPLE 18 Salt of trifluoroacetic acid from (2-cyclopent-1-enyl-4-piperidin-4-yl-phenylenediamine) 4-cyano-1 H-imidazole-2-carboxylic acid H The title compound was prepared from the salt of potassium 4-cyano-1- (2-trimethylsilyl-ethoxymethyl) -1 H-imidazole-2-carboxylate (as prepared in Example 3, step (d)) and 4- (4-amino-3-cyclopent-1-enyl-phenyl) -piperidin-1-carboxylic acid tert-butyl ester (prepared according to the procedure in Example 13, step (d), substituting the acid cyclopentene-1-yl boronic acid by cyclohex-1-enyl boronic acid) according to the procedure for Example 14. 1 H NMR (400 MHz, DMSO-d 6) d 14.25 (broad s, 1 H), 10.00 (s, 1 H), 8.36 (s, 1 H), 7.72 (d, 1 H), 7.18 (m, 2 H), 6.06 (s, 1 H), 4.12 (m, 1 H), 3.42 (m, 2 H), 3.18 (m, 2H), 3.00 (m, 3H), 2.80 (m, 2H), 1.92 (m, 5H). Mass spectrum (ESI, m / z): calculated for C21 H23N5O, 362.2 (M + H), found 362.2.

EXAMPLE 19 An alternative method for the synthesis of the intermediate described in Example 1 is described below. 5-cyano-furan-2-carboxylic acid A 250 ml_, three-necked round bottom flask equipped with a mechanical stirrer, a heating blanket and a condenser was charged with 5-formyl-2-furancarboxylic acid (9.18 g)., 65.6 mmoles) and pyridine (60 ml_). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added, and the mixture was heated to 85 ° C. Acetic anhydride (40 mL) was added and the reaction was stirred at 85 ° C for 3 hours, after which time the solvent was evaporated at 40 ° C under reduced pressure. The residue was dissolved in water, basified with 2.0 N NaOH solution to pH 9 and extracted with 4: 1 dichloromethane / 2-propanol until the pyridine was completely removed (5 x 200 mL). The aqueous solution was then acidified with a 2.0 N HCl solution to pH 2, saturated with solid NaCl and extracted with 4: 1 dichloromethane / 2-propanol (5 x 200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to dryness. The residue was crystallized from dichloromethane to provide 6.80 g of compound of the title as a white solid (76%). Mass spectrum (ESl-neg, m / z) calculated for C6H3N03, 136.0 (M-H), found 136.1. The H NMR spectrum was consisted of the assigned structure.

EXAMPLE 20 { 4-Cyano-1H-imidazole-2-carboxylic acid 2-cyclohex-1-enyl-4- [1- (2-methanesulfonyl-acetyl) -pperperine-4-yl-phenyl) -amide One flask was charged with methanesulfonylacetic acid (14 mg, 0.10 mmol), EDCI (30 mg, 0.15 mmol), HOBt (14 mg, 0.10 mmol), DIEA (36 pL, 0.20 mmol) and 0.5 mL of DCM and stirred at 25 ° C. After 10 minutes, a solution containing the TFA salt of the 4-cyano-H-imidazole-2- (2-cyclohex-1-yl-4-piperidin-4-yl-phenyl) -amide was added. carboxylic (40 mg, 0.08 mmol) (as prepared in Example 20, step (b)) and NEt3 (14 μl, 0.09 mmol) in 0.5 mL of DCM, and the reaction was allowed to proceed for 10 hours at 25 ° C . The reaction mixture was loaded into a 5 g SPE cartridge (silica), and the title compound was eluted with 10% EtOH / EtOAc to provide 10 mg (25%) of a white solid. 1 H NMR (400 MHz, CDCl 3): d 1 1.60 (broad s, 1 H), 9.52 (s, 1 H), 8.30 (d, 1 H), 7.74 (s, 1 H), 7.60 (dd, 1 H ), 7.03 (d, 1 H), 5.86 (m, 1 H), 4.84 (m, 1 H), 4.18 (s, 2 H), 4.12 (m, 1 H), 3.32 (m, 1 H), 3.20 (s, 3H), 2.82 (m, 2H), 2.30 (m, 4H), 1.98 (m, 2H), 1.84 (m, 5H), 1.72 (m, 1 H). Mass spectrum (ESI, m / z): calculated for C25H29N5O4S, 496.2 (M + H), found 496.2.

EXAMPLE 21 Salt of trifluoroacetic acid of f2-cyclohex-1-enyl-4- (1-pyridin-2-ylmethyl-piperidin-4-yl) -phene-4-cyano-1H-imidazole-2-carboxylic acid A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (88 mg, 0.18 mmole) (as prepared in Example 14, step (b)), pyridine-2-carbaldehyde (17 μ? _, 0.21 mmol), NEt3 (30 μ? _, 0.21 mmol), Sodium triacetoxyborohydride (56 mg, 0.25 mmol) and 0.8 ml of 1,2-dichloroethane and stirred for 10 hours at 25 ° C. The solvent was evaporated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA / H20 for 20 minutes, to give 81 mg (78%) of a white solid . H NMR (400 MHz, DMSO-d6): d 14.25 (broad s, 1 H), 9.90 (s broad, 1 H), 9.79 (s, 1 H), 8.72 (s, 1 H), 8.36 (s, 1 H), 7.98 (m, 1 H), 7.88 (dd, 1 H), 7.58 (d, 1 H), 7.52 (m, 1 H), 7.20 (m, 1 H), 7.12 (d, 1 H) ), 5.76 (m, 1 H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1 H), 2.20 (m, 4H), 2.00 (m, 4H), 1.72 (m, 4H). Mass spectrum (ESI, m / z): calculated for C28H3oN60, 467.2 (M + H), found 467.2.

EXAMPLE 22 Salt of trifluoroacetic acid of 4- (4-methyl-cyclohex-1-enyl) -4- (1-pyridin-2-ylmethyl-piperidin-4-yl) -phenyl-amide of 4-acid. cyano-1 H-imidazole-2-carboxylic acid This compound was prepared according to the procedure in Example 21 from [2- (4-methyl-cyclohex-1-yl) -4-piperidin-4-yl-phenyl] -amide of 4-cyano- 1 H-imidazole-2-carboxylic acid (as prepared in Example 17) and pyridine-2-carbaldehyde. 1 H NMR (400 MHz, DMSO-d 6): d 14.25 (broad s, 1 H), 9.90 (broad s, 1 H), 9.79 (s, 1 H), 8.72 (s, 1 H), 8.36 (s, 1 H), 7.98 (m, 1 H), 7.86 (dd, 1 H), 7.54 (d, 1 H), 7.52 (m, 1 H), 7.20 (m, 1 H), 7.12 (d, 1 H) ), 5.74 (m, 1 H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1 H), 2.48-2.22 (m, 3H), 2.18- 2.06 (m, 4H), 1.98-1.82 (m, 3H), 1.52 (m, 1 H), 1.02 (s, 3H). Mass spectrum (ESI, m / z): calculated for C28H32N60, 481.2 (M + H), found 481.2.

EXAMPLE 23 Salt of the trifluoroacetic acid of the (2-cyclopent-1-enyl-4- [1- (1-methyl-1H-imidazol-2-ylmethyl) -piperidin-4-in-phenyl) -amide of the acid -cyano-1 H- imidazole-2-carboxylic acid This compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl) -amide (as was prepared in Example 18) and 1-methyl-1 H-imidazole-2-carbaldehyde according to the procedure in Example 21. 1 H NMR (400 MHz, CD3OD): d 8.03 (m, 2H), 7.50 (d , 1 H), 7.42 (s, 1 H), 7.20 (m, 2H), 6.02 (m, 1 H), 4.22 (s, 2H), 3.96 (s, 3H), 3.30 (m, 2H), 2.82 -2.40 (m, 7H), 2.13-1.84 (m, 6H). Mass spectrum (ESI, m / z): calculated for C 26 H 29 N 7 O, 456.2 (M + H), found 456.2.

EXAMPLE 24 Amide of 4- acid. { 4-r (4-cyano-1H-imidazole-2-carbonyl) -amino1-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (51 mg, 0.10 mmole) (as prepared in Example 14, step (b)), NEt3 (22 pl_, 0.15 mmole), trimethylsilyl isocyanate (16 pL, 0.11 mmole) and 1.0 mL of DCM and it was stirred for 10 hours at 25 ° C. The solvent was evaporated and the title compound was purified by RP-HPLC (C18), eluting with 35-60% CH3CN in 0.1% TFA / H2O for 11 minutes, to provide 30 mg (70%) of a solid White. 1 H NMR (400 MHz, DMSO-d 6): d 14.28 (broad s, 1 H), 9.76 (s, 1 H), 8.34 (s, 1 H), 7.84 (d, 1 H), 7.18 (dd, 1 H), 7.08 (d, 1 H), 6.00 (broad s, 2H), 5.72 (m, 1 H), 4.18 (m, 2H), 2.80-2.60 (m, 3H), 2.24-2.10 (m, 4H) ), 1.80-1.60 (m, 6H), 1.50 (m, 2H). Mass spectrum (ESI, m / z): calculated for C23H26N60, 419.2 (M + H), found 419.0.

EXAMPLE 25 Salt of trifluoroacetic acid of f2-cyclohex-1-enyl-4- (3,4,5,6-tetrahydro-2H-M 12'1-bipyridinyl-1-yl) -phenin-amide of 4-cyano-1 H acid -imidazole-2-carboxylic A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (75 mg, 0. 15 mmol) (as prepared in Example 14, step (b)), K2C03 (84 mg, 0.60 mmol), 2-fluoropyridine (27 μ? _, 0.30 mmol) and 0.3 mL of?,? - dimethylacetamide, and it was stirred for 8 hours at 120 ° C. The reaction was diluted with 3 mL of H20 and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA / H2O for 9 minutes, to give 50 mg (75% ) of a white solid. H NMR (400 MHz, CD3OD): d 8.18 (d, 1 H), 8.06 (m, 1 H), 8.02 (s, 1 H), 7.94 (dd, 1 H), 7.48 (d, 2 H), 7.22 (dd, 1 H), 7.12 (d, 1 H), 6.98 (t, 1 H), 5.82 (m, 1 H), 4.32 (m, 2H), 3.46 (m, 2H), 3.00 (m, 1 H), 2.30 (m, 4H), 2.18 (m, 2H), 1.96-1.74 (m, 6H). Mass spectrum (ESI, m / z): calculated for C27H28N60, 453.2 (M + H), found 453.2.

EXAMPLE 26 Salt of trifluoroacetic acid from 4-cyano-1 H-imidazole (2-cyclohex-1-enyl-4-f1- (2-hydroxy-ethyl) -piperidin-4-yl] -phenyl) -amide -2-carboxylic The title compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide ( as prepared in Example 14, step (b)) and hydroxy-acetaldehyde according to the procedure in Example 21. H NMR (400 MHz, CD3OD): d 8.18 (d, 1 H), 8.02 (s, 1 H), 7.22 (dd, 1 H), 7.14 (d, 2H), 5.82 (m, 1 H), 3.94 (m, 2H), 3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t , 2H), 2.92 (m, 1 H), 2.30 (m, 4H), 2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m / z): calculated for C 24 H 29 N 5 O 2, 420.2 (M + H), found 420.2.

EXAMPLE 27 Salt of trifluoroacetic acid of 4-cyano-1H-imidazole-2- (2-cyano-ethyl) -piperidin-4-iri-2-cyclohex-1-enyl-phenyane-4-cyano-1H-imidazole-2-acid carboxylic A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phen-1-yl) -amide (77 mg, 0.16 mmole) (as prepared in Example 14, step (b)), NEt3 (24 μ? _, 0.16 mmoles), acrylonitrile (12 μ? _, 0.18 mmoles), 0.1 mL of MeOH and 1.0 mL of 1,2-dichloroethane and stirred for 1 hour at 80 ° C. The reaction was concentrated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA / H2O for 12 minutes, to afford 83 mg (95%) of a white solid . 1 H NMR (400 MHz, CD 3 OD): d 8.18 (d, 1 H), 8.06 (m, 1 H), 7.22 (dd, 1 H), 7.12 (d, 1 H), 5.82 (m, 1 H), 3.76 (m, 2H), 3.60 (m, 2H), 3.28 (t, 2H), 3.12 (t, 2H), 2.92 (m, 1 H), 2.30 (m, 4H), 2.18-1.98 (m, 4H) ), 1.92-1.74 (m, 4H). Mass spectrum (ESI, m / z): calculated for C25H28N6O, 429.2 (M + H), found 429.2.

EXAMPLE 28 Salt of trifluoroacetic acid f4- (1-carbamoylmethyl-piperidin-4-yl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1H-imidazole-2-carboxylic acid A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (50 mg, 0.10 mmole) (as prepared in Example 14, step (b)), NEt3 (32 μ? _, 0.23 mmole), 2-bromoacetamide (16 mg, 0.12 mmole) and 0.5 mL of DCM and stirred for 4 hours at 25 ° C. The reaction was concentrated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA / H20 for 12 minutes, to provide 42 mg (75%) of a white solid . 1 H NMR (400 MHz, DMSO-d 6): d 14.28 (broad s, 1 H), 9.78 (s, 1 H), 9.50 (broad s, 1 H), 8.34 (s, 1 H), 8.00 (s, 1 H), 7.88 (d, 1 H), 7.72 (s, 1 H), 7.18 (dd, 1 H), 7.10 (d, 1 H), 5.76 (m, 1 H), 3.94 (s, 2 H) , 3.58 (m, 2H), 3.12 (m, 2H), 2.80 (m, 1 H), 2.20 (m, 4H), 1.98 (m, 4H), 1.80 (m, 4H). Mass spectrum (ESI, m / z): calculated for C 24 H 28 N 6 O 2, 433.2 (M + H), found 433.2.

EXAMPLE 29 Salt of the trifluoroacetic acid of (2-cyclohex-1-enyl-4- [1- (2-pyridin-2-yl-acetyl) -p-perpent-4-n-phenyl) -amide of the 4-cyano-1H-imidazole-2-carboxylic acid A flask was charged with the TFA salt of the 4-cyano-1 H-imidazole (2-cyclohex-1-enyl-4-pperiodine-4-yl-phenyl) -amide. 2-carboxylic acid (25 mg, 0.05 mmol) (as prepared in Example 14, step (b)), pyridin-2-yl-acetic acid hydrochloride (10 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol) ), HOBt (8.0 mg, 0.06 mmol), DIEA (36 μ? _, 0.20 mmol) and 0.2 mL of DMF and stirred at 25 ° C for 10 hours. The reaction was diluted with 2 mL of H2O and the title compound was purified by RP-HPLC (C18), with 30-50% CH3CN in 0.1% TFA / H2O for 9 minutes, to give 22 mg (70% ) of a white solid. 1 H NMR (400 MHz, CD 3 OD): d 8.82 (d, 1 H), 8.52 (t, 1 H), 8.14 (d, 1 H), 8.04 (s, 1 H), 7.96 (m, 3 H), 7.20 (dd, 1 H), 7.10 (d, 1 H), 5.82 (m, 1 H), 4.68 (m, 1 H), 4.32 (m, 2H), 4.18 (m, 1 H), 3.40 (m, 1 H), 2.88 (m, 2H), 2.30 (m, 4H), 2. 06-1 .60 (m, 8H). Mass spectrum (ESI, miz): calculated for C29H30N6O2, 495.2.2 (M + H), found 495.2.

EXAMPLE 30 Salt of trifluoroacetic acid of 4-cyano-1 (2-cyclohex-1-enyl-4-ri- (2-pyridin-3-yl-acetyl) -piperidin-4-in-phenyl) -amide of 4-cyano-1 acid H-imidazole-2-carboxylic acid The title compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-pperiodin-4-yl-phenyl] -amide (as prepared in Example 14, step (b)), according to the procedure in Example 29, using pyridin-3-yl-acetic acid. H NMR (400 MHz, CD3OD): d 8.80 (m, 2H), 8.54 (d, 1 H), 8.10 (d, 1 H), 8.06 (t, 1 H), 7.98 (s, 1 H), 7.18 (dd, 1 H), 7.08 (d, 1 H), 5.78 (m, 1 H), 4.68 (m, 1 H), 4.20 (m, 1 H), 4.18 (s, 2 H), 3.36 (m, 1 H), 2.84 (m, 2H), 2.28 (m, 4H), 2.06-1.70 (m, 7H), 1.62 (m, 1 H). Mass spectrum (ESI, m / z): calculated for C29H30N6O2, 495.2 (M + H), found 495.2.

EXAMPLE 31 Salt of trifluoroacetic acid from (2-cyclohex-1-enyl-4- [1- (2-pyridin-4-yl-acetyl) -piperidin-yl] -phenyl} -amide of 4-cyano acid -1H-imidazole-2-carboxylic acid The title compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole- (2-cyclohex-1-ene-4-piperidin-4-yl-phenyl) -amide. 2-carboxylic acid (as prepared in Example 14, step (b)), according to the procedure in Example 29, using pyridin-4-yl-acetic acid. H NMR (400 MHz, CD3OD): d 8.78 (d, 2H), 8.12 (d, 1 H), 8.00 (m, 3H), 7.18 (dd, 1 H), 7.08 (d, 1 H), 5.80 ( m, 1 H), 4.66 (m, 1 H), 4.22 (s, 2H), 4.18 (m, 1 H), 3.34 (m, 1 H), 2.84 (m, 2H), 2.24 (m, 4H) , 2.00-1.70 (m, 7H), 1.64 (m, 1 H). Mass spectrum (ESI, m / z): calculated for C29H30N6O2, 495.2 (M + H), found 495.2.

EXAMPLE 32 Salt of trifluoroacetic acid from (2-cyclohex-1-enyl-4- { 1- [2- (1-metit-1 H- imidazol-4-yl) -acetin-piperidin-4-yl) 4-cyano-1H-imidazole-2-carboxylic acid phenyl) -amide The title compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole- (2-cyclohex-1-enyl-4-piperidin-4-yl-phenol) -amide. 2-carboxylic acid (as prepared in Example 14, step (b)), according to the procedure in Example 29, using (1-methyl-1 H-imidazol-4-yl) -acetic acid. 1 H NMR (400 MHz, CD 3 OD): d 8.82 (s, 1 H), 8.10 (d, 1 H), 8.00 (s, 1 H), 7.42 (s, 1 H), 7.16 (dd, 1 H), 7.06 (d, 1 H), 5.80 (m, 1 H), 4.66 (m, 1 H), 4.12 (m, 1 H), 4.04 (m, 2H), 3.92 (s, 3H), 3.28 (m, 1 H), 2.82 (m, 2H), 2.26 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1 H). Mass spectrum (ESI, m / z): calculated for C28H31 N7O2, 498.2 (M + H), found 498.2.

EXAMPLE 33 Salt of trifluoroacetic acid of. { 2-cyclohex-1-enyl-4- [1- (2-1H-imidazol-4-yl-acetyl) -piperidin-4-in-phenyl} 4-cyano-1H-imidazole-2-carboxylic acid amide The title compound was prepared from the TFA salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide ( as prepared in Example 14, step (b)), according to the procedure in Example 29, using (1-methyl-1 H-imidazol-4-yl) -acetic acid. 1 H NMR (400 MHz, CD 3 OD): d 8.88 (s, 1 H), 8.12 (d, 1 H), 8.02 (s, 1 H), 7.44 (s, 1 H), 7.20 (dd, 1 H), 7.10 (d, 1 H), 5.82 (m, 1 H), 4.70 (m, 1 H), 4.18 (m, 1 H), 4.06 (m, 2 H), 3.36 (m, 1 H), 2.84 (m , 2H), 2.30 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1 H). Mass spectrum (ESI, m / z): calculated for C27H29N7O2, 484.2 (M + H), found 484.2.

EXAMPLE 34 Salt of difluoroacetic acid (2-cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-ethyl) -piperidin-4-phenyl} -amide of 4-cyano acid -1H-imidazole-2-carboxylic acid a) (2-cyano-1- (2-dimethyl-silyl-) 2-cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-ethyl) -piperidin-4-in-phenyl) -amide ethoxymethyl) -1 H-imidazole-2-carboxylic acid A flask was charged with TFA salt of the (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -H acid. -imidazole-2-carboxylic acid (830 mg, 1.34 mmol) (as prepared in Example 39, step (a)), K2C03 (600 mg, 4.34 mmol), sodium iodide (40 mg, 0.27 mmol), hydrochloride 4- (2-chloro-ethyl) -morpholine (260 mg, 1.40 mmol) and 5.0 ml of N, N-dimethylacetamide, and stirred for 8 hours at 80 ° C. The reaction was diluted with EtOAc (50 mL) and washed with NaHCO3 (2 x 50 mL_), brine (50 mL) and concentrated. The title compound was purified by flash chromatography (silica gel, 5% MeOH / DCM) to give 650 mg (78%) of a white solid. Mass spectrum (ESI, m / z): calculated for C34H50N6O3 Si, 619.4 (M + H), found 619.3. b) trifluoroacetic acid salt of 4-cyano- (2-cyclohex-1-enyl-4- [1- (2-morpholin-4-yl-ethyl) -piperidin-4-yl-phenyl) -amide 1 H-imidazole-2-carboxylic acid to a solution of the. { 2-cyclohex-1-enyl-4- [1 - (2-morpholin-4-yl-ethyl) -piperidin-4-yl] -phenyl} 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid amide (650 mg, 1.05 mmol) (as prepared in the previous step) in 10 mL of DCM, they added 0.3 mL of EtOH and 3.0 mL of TFA, and the reaction was allowed to proceed for 2 hours at 25 ° C. The reaction was diluted with 10 mL of EtOH and concentrated. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA / H2O for 9 minutes, to provide 600 mg (80%) of a white solid. 1 H NMR (400 MHz, CD 3 OD): d 8.18 (d, 1 H), 8.04 (s, 1 H), 7.24 (dd, 1 H), 7.14 (d, 1 H), 5.84 (m, 1 H), 3.84 (m, 4H), 3.76 (m, 2H), 3.50 (m, 2H), 3.30-3.10 (m, 4H), 2.92 (m, 5H), 2.30 (m, 4H), 2.20-2.00 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m / z): calculated for C28H36N602, 489.2, found 489.2.

EXAMPLE 35 G2- (1, 1-dioxo-1, 2,3,6-tetrahydro-1 / .6-thiopyran-4-yl) -4-piperidin-4-yl-phen-amide of 4-acid cyano-1 H-imidazole-2-carboxylic acid a) 3,6-Dihydro-2H-thiopyran-4-yl ester of trifluoromethanesulfonic acid A solution of tetrahydro-thiopyran-4-one (1.00 g, 8.61 mmol) in 10 mL of THF was added to a solution of LDA (2.0 M, 4.52 mL, 9.04 mmol) in 20 mL of THF at -78 ° C. under Ar. The mixture was warmed to room temperature and stirred for 0.5 hours, then cooled again to -78 ° C. A solution of N-Phenyltrifluoromethanesulfonimide (3.42 g, 9.47 mmol) in 10 mL of THF. The The resulting mixture was warmed to room temperature and stirred for 0.5 hours under Ar. It was treated with 200 ml of EtOAc, the mixture was washed with H20 (3 x 50 ml), brine (50 ml) and dried (Na 2 SO 4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (hexane-3% EtOAc / hexane) gave 810 mg (38%) of the title compound as a colorless oil. 1 H NMR (CDCl 3, 400 MHz): d 6.01 (m, 1 H), 3.30 (m, 2 H), 2.86 (dd, 2 H, J = 5.7, 5.7 Hz), 2.58-2.64 (m, 2 H). Mass spectrum (ESI, m / z): calculated for C6H7F3O3S2, 249.0 (M + H), found 249.3.

A mixture of 4-nitrophenylboronic acid (418 mg, 2.50 mmol), 3,6-dihydro-2H-thiopyran-4-yl ester of trifluoromethanesulfonic acid (as prepared in the previous step, 931 mg, 3.75 mmol), Pd ( PPh3) 4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1,4-dioxane were added to a 2.0 M aqueous Na 2 CO 3 solution (3.13 mL, 6.25 mmol) . The resulting mixture was stirred at 80 ° C for 2 hours and then cooled to room temperature. It was treated with 200 mL of EtOAc, the mixture was washed with H2O (2 x 30 mL), brine (30 mL) and dried (Na2SO4). The elimination of the solvent under reduced pressure followed by Flash chromatography of the residue on silica gel (1-3% EtOAc / hexane) gave 470 mg (85%) of the title compound as a light brown oil. 1 H NMR (CDCl 3, 400 MHz): d 8.19 (d, 2 H, J = 9.1 Hz), 7.48 (d, 2 H, J = 9.1 Hz), 6.36 (m, 1 H), 3.39 (m, 2 H), 2.91 (t, 2H, J = 5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI, m / z): calculated for C-nH-nNO ^, 222.1 (M + H), found 222.3. c) 1, 1-4- (4-Nitro-phenyl) -3,6-dihydro-2H-thiopyran dioxide A solution of 3-chloroperoxybenzoic acid (1.04 g, 4.62 mmol, 77%) in 15 mL of dichloromethane (DCM) was slowly added to a solution of 4- (4-nitro-phenyl) -3,6-dihydro-2H- thiopyran (as prepared in the previous step, 465 mg, 2.10 mmol) in 15 mL of DCM at -78 ° C under Ar. The mixture was stirred at -78 ° C for 0.5 hours and then warmed to room temperature. It was treated with 100 mL of EtOAc, the mixture was washed with 10% Na 2 SO 3 (2 x 15 mL), a saturated aqueous NaHCO 3 solution (20 mL), H 2 O (20 mL), brine (20 mL) and dried ( Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc / DCM) gave 518 mg (97%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 8.23 (d, 2 H, J = 9.0 Hz), 7.52 (d, 2 H, J = 9.0 Hz), 6.04 (m, 1 H), 3.86 (m, 2 H), 3.26 -3.31 (m, 2H), 3.18-3.23 (m, 2H). d) 4- (1 l1-Dioxo-hexahydro-1 6-thiopyran-4-yl) -phenylamine A mixture of 1,1-4- (4-nitro-phenyl) -3,6-dihydro-2H-thiopyran dioxide (as prepared in the previous step, 502 mg, 1.98 mmole) and Pd / C at 10% (250 mg, 50% by weight) in 15 mL of MeOH was stirred at room temperature under H2 (balloon pressure) for 2 hours. The Pd catalyst was removed by filtration over Celite, and the filtrate was concentrated to provide 314 mg (70%) of the title compound as a light yellow solid. 1 H NMR (CDCl 3, 400 MHz): d 7.03 (d, 2 H, J = 8.3 Hz), 6.67 (d, 2 H, J = 8.3 Hz), 3.51 -3.79 (broad s, 2 H), 3.1 1 -3.17 (m , 4H), 2.70 (dddd, 1 H, J = 12.3, 12.3, 2.9, 2.9 Hz), 2.31-2.43 (m, 2H), 2.15-2.23 (m, 2H). e) 2-Bromo-4- (1,1-dioxo-hexahydro-1 6-thiopyran-4-yl) phenylamine To a suspension of 4- (1,1-dioxo-hexahydro-6-thiopyran-4-yl) -phenylamine (as prepared in the previous step, 174 mg, 0.77 mmol) in 20 mL of 3: 1 DCM / MeOH at 0 ° C, N-bromosuccinimide (NBS) (137 mg, 0.77 mmol) in 5 mL of DCM under Ar was added. The mixture was warmed to room temperature and stirred for 1 hour under Ar. It was treated with 100 mL of EtOAc, the mixture was washed with H2O (2 x 20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-3% EtOAc / DCM) gave 155 mg (66%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 7.28 (d, 1 H, J = 2.0 Hz), 6.97 (dd, 1 H, J = 8.3, 2.0 Hz), 6.73 (d, 1 H, J = 8.3 Hz) , 4.07 (s broad, 2H), 3.09-3.14 (m, 4H), 2.66 (dddd, 1 H, J = 12.1, 12.1, 3.3, 3.3 Hz), 2.26-2.39 (m, 2H), 2.12-2.21 ( m, 2H). Mass spectrum (ESI, m / z): calculated for C 1 H 14 BrN02Sl 304.0 (M + H), found 304.1. f) 2-Cyclohex-1-enyl-4- (, 1-dioxo-hexahydro-1 6-thiopyran-4-yl) -phenylamine A mixture of 2-bromo-4- (1,1-dioxo-hexahydro- ^ 6-thiopyran-4-yl) -phenylamine (as prepared in the previous step), 150 mg, 0.493 mmol), cyclohexen-1-yl-boronic acid (70 mg, 0.542 mmol) and Pd (PPh3) 4 (57 mg, 0.0493 mmol) in 5 mL of 1,4-dioxane was added to a solution aqueous Na2CO3 2.0 M (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80 ° C for 8 hours under Ar and then cooled to room temperature. It was treated with 50 mL of EtOAc, the mixture was washed with H 2 O (3 x 15 mL), brine (20 mL) and dried (Na 2 SO 4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc / DCM) gave 130 mg (86%) of the title compound as a brown solid. 1 H NMR (CDCl 3; 400 MHz): d 6.89 (dd, 1 H, J = 8.4, 2.3 Hz), 6.84 (d, 1 H, J = 2.3 Hz), 6.65 (d, 1 H, J = 8.4 Hz), 5.74 (m, 1 H), 3.74 (broad s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1 H, J = 12.1, 12.1, 3.1, 3.1 Hz), 2.29-2.42 (m, 2H), 2.13 -2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73 (m, 2H). Spectrum of masses (ESI, m / z): calculated for C-17H23NO2S, 306.1 (M + H), found 306.1. g) [2-cyclohex-1-enyl-4- (1,1-dioxo-hexahydro-1-6-thiopyran-4-yl) -phenyl-amide of 4-cyano-1- (2-trimethylsilanyl) ethoxymethyl) -1 H-imidazole-2-carboxylic acid To a mixture of 2-cyclohex-1-enyl-4- (1,1-dioxo-hexahydro-1,6-thiopyran-4-yl) -phenylamine (as prepared in the previous step, 122 mg, 0.50 mmol ), Potassium 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carboxylate (as prepared in Example 3, step (d), 134 mg, 0.44 mmole) and bromotri hexafluorophosphate (pyrrolidino) phosphono (PyBroP) (205 mg, 0.44 mmoles) in 5 mL of DMF was added DIEA (209 μ? _, 1.20 mmol). The resulting mixture was stirred at room temperature for 18 hours under Ar, cooled to room temperature. It was treated with 50 mL of EtOAc, the mixture was washed with H20 (3 x 10 mL), brine (10 mL) and dried (Na2SO4). The elimination of the solvent under reduced pressure followed by chromatography Instantaneous residue on silica gel (1 -3% EtOAc / DCM), gave 161 mg (73%) of the title compound as a colorless oil. H NMR (CDCl 3, 400 MHz): d 9.69 (s, 1 H), 8.29 (d, 1 H, J = 8.4 Hz), 7.78 (s, 1 H), 7.14 (dd, 1 H, J = 8.4, 2.2 Hz), 7.04 (d, 1 H, J = 2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1 H), 3.66 (t, 2H, J = 8.2 Hz), 3.1 1 -3.20 (m , 4H), 2.77 (dddd, 1 H, J = 12.1, 12.1, 3.2, 3.2 Hz), 2.35-2.47 (m, 2H), 2.17-2.33 (m, 6H), 1 .74- 1 .89 (m , 4H), 0.97 (t, 2H, J = 8.2 Hz), 0.00 (s, 9H). Mass spectrum (ESI, miz): calculated for C28H38N4O4SSI, 555.2 (M + H), found 555.3. h) f2-cyclohex-1-enyl-4- (1,1-dioxo-hexahydro-1? 6-??????????????????? -2-carboxylic To a solution of 4-cyano-1 - (2- (2-cyclohex-1-enyl-4- (1,1-dioxo-hexahydro-1-6-thiopyran-4-yl) -phenyl) -amide) trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step, 145 mg, 0.261 mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2 mL of TFA. The resulting solution was stirred at room temperature for 3 hours. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-25% of EtOAc / DCM), gave 83 mg (90%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 12.34 (s, 1 H), 9.60 (s, 1 H), 8.35 (d, 1 H, J = 8.4 Hz), 7.75 (s, 1 H), 7.30 (dd, 1 H, J = 8.4, 2.2 Hz), 7.08 (d, 1H, J = 2.2 Hz), 5.86 (m, 1H), 3.11-3.23 (m, 4H), 2.80 (dddd, 1H, J = 12.2, 12.2, 28, 2.8 Hz), 2.40-2.57 (m, 2H), 2.17-2.35 (m, 6H), 1.74-1.91 (m, 4H). Mass spectrum (ESI, m / z): calculated for C22H24N4O3S, 425.2 (M + H), found 425.6.

EXAMPLE 36 Salt of trifluoroacetic acid from [2- (1,1-dioxo-1,2,3,6-tetrahydro-1 6-thiopyrn-4-yl) -4-piperidin-4-yl-phenol 4-cyano-1H-imidazole-2-carboxylic acid n-amide TFA a) 2- (3,6-Dihydro-2H-thiopyran-4-yl) -5,5-dimethyl-f1, 3,2ldioxaborin A mixture of the trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in Example 35, step (a), 500 mg, 2.01 mmol), diborium bis (neopentyl glycolate) (478 mg , 2.1 1 mmol), Pd (dppf) CI2 (147 mg, 0.20 mmol) and KOAc (592 mg, 6.03 mmol) in 8 mL of 1,4-dioxane was stirred at 80 ° C for 8 hours under Ar, and then it was cooled to room temperature. It was treated with 50 mL of EtOAc, the mixture was washed with H20 (2 x 10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0-5% EtOAc / DCM) gave 351 mg (82%) of the title compound as a colorless oil. 1 H NMR (CDCl 3, 400 MHz): d 6.62 (m, 1 H), 3.63 (s, 4 H), 3.21 (m, 2 H), 2.68 (t, 2 H, J = 5.8 Hz), 2.37 (m, 2 H) 0.96 (s, 6H). Mass spectrum (ESI, m / z): calculated for C10H17BO2S, 213.1 (+ H), found 213.1. b) 4- [4-amino-3- (3,6-dihydro-2H-thiopyran-4-yl) -phene-piperidin-1-carboxylic acid tert -butyl ester) A mixture of the 4- (4-amino-3-bromo-phenyl) -piperidin-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563 mmol), - (3,6-dihydro-2H-thiopyran-4-yl) -5,5-dimethyl- [1, 3,2] dioxaborin (as prepared in the previous step, 131 mg, 0.619 mmol) and Pd (PPh3 ) 4 (65 mg, 0.056 mmol) in 5 ml_ of 1,4-dioxane was added to an aqueous 2.0 M Na 2 CO 3 solution (2.25 ml_, 4.5 mmol). The resulting mixture was stirred at 80 ° C for 7 hours under Ar and then cooled to room temperature. It was treated with 50 ml_ of EtOAc, the mixture was washed with H20 (3 x 15 ml_), brine (20 ml_) and dried (Na2S0). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (15-30% EtOAc / hexane) gave 141 mg (67%) of the title compound as a colorless oil. H NMR (CDCl 3, 400 MHz): d 6.91 (dd, 1 H, J = 8.2, 2.2 Hz), 6.81 (d, 1 H, J = 2.2 Hz), 6.65 (d, 1 H, J = 8.2 Hz), 5.91 (m, 1 H), 4.22 (broad s, 2H), 3.66 (broad s, 2H), 3.29 -3.31 (m, 2H), 2.87 (dd, 2H, J = 5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56 (m, 3H), 1.78 (d, 2H, J = 12.6 Hz), 1.50-1 .63 (m, 2H), 1 .48 (s, 9H). Mass spectrum (ESI, miz): calculated for C21H30N2O2S, 375.2 (M + H), found 375.2. c) 4- [4 - ([4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl-amino) -3- (3,6-dihyl) -butyl ester dro-2H-thiopyran-4-yl) -pheni-piperidin-1-carboxylic acid A mixture of 4- [4-amino-3- (3,6-dihydro-2H-thiopyran-4-yl) -phenyl] -piperidin-1-carboxylic acid tert-butyl ester (as prepared in the previous step) , 45 mg, 0.12 mmol), 4-cyano-1 - (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carboxylate potassium (as prepared in Example 3, step (d), 44 mg , 0.144 mmol) and PyBroP (67 mg, 0.144 mmol) in 2 mL of DMF, was added to DIEA (42 pL, 0.24 mmol). The resulting mixture was stirred at room temperature for 4 hours under Ar. It was treated with 30 mL of EtOAc, the mixture was washed with H20 (3 x 10 mL), brine (10 mL) and dried (Na2S04). The elimination of the solvent under reduced pressure followed by chromatography The residue on silica gel (1-2% EtOAc / DCM), afforded 64 mg (85%) of the title compound as a light yellow oil. H NMR (CDCl 3, 400 MHz): d 9.51 (s, 1 H), 8.21 (d, 1 H, J = 8.5 Hz), 7.78 (s, 1 H), 7.16 (dd, 1 H, J = 8.5, 2.1 Hz), 7.02 (d, 1 H, J = 2.1 Hz), 6.00 (m, 1 H), 5.92 (s, 2H), 4.25 (broad s, 2H), 3.66 (t, 2H, J = 8.2) , 3.42 (m, 2H), 2.93 (dd, 2H, J = 5.7, 5.7 Hz), 2.79 (m, 2H), 2.63 (dddd, 1 H, J = 12.3, 12.3, 3.3, 3.3 Hz), 2.49- 2.56 (m, 2H), 1.82 (d, 2H, J = 12.8 Hz), 1.56-1.66 (m, 2H), 1.49 (s, 9H), 0.97 (t, 2H, J = 8.2 Hz), 0.00 (s) , 9H). d) Ter-Butyl ester of 4- [4-. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -imidazole-2-carbonyl-amino) -3- (1,1-dioxo-1, 2,3,6-tetrahydro-6) -thiopyran-4-yl) -fenin-piperidine-1-carboxylic acid A solution of 3-chloroperoxybenzoic acid (91 mg, 0.404 mmol, 77%) in 1 mL of DCM was slowly added to the ter-butyl ester of 4- [4- acid. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carbonyl] - Not me} -3- (3,6-Dihydro-2H-thiopyran-4-yl) -phenyl] -piperidine-1-carboxylic acid (as prepared in the previous step, 120 mg, 0.192 mmol) in 3 mL of DCM at -78 ° C under Ar. The mixture was stirred at -78 ° C for 5 minutes, and then warmed to room temperature. It was treated with 40 mL of EtOAc, the mixture was washed with 15% Na2SO3 (5 mL), a saturated aqueous solution of NaHCO3 (2 x 10 mL), H2O (10 mL), brine (10 mL) and dried ( Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-10% EtOAc / DCM) afforded 85 mg (67%) of the title compound as a colorless oil. 1 H NMR (CDCl 3, 400 MHz): d 9.23 (s, 1 H), 8.03 (d, 1 H, J = 8.3 Hz), 7.80 (s, 1 H), 7.21 (dd, 1 H, J = 8.3, 2.0 Hz), 7.06 (d, 1 H, J = 2.0 Hz), 5.93 (s, 2H), 5.75 (t, 1 H, J = 4.1 Hz), 4.25 (broad s, 2H), 3.86 (broad s, 2H), 3.66 (t, 2H, J = 8.2 Hz), 3.29 (t, 2H, J = 6.3 Hz), 3.03 (t, 2H, J = 5.4 Hz), 2.74-2.86 (m, 2H), 2.64 (dddd, 1 H, J = 12.3, 12.3, 3.3, 3.3 Hz), 1.82 (d, 2H, J = 12.3 Hz), 1 .55-1.65 (m, 2H), 1.49 (s, 9H), 0.98 (t, 2H, J = 8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m / z): calculated for C32H45N506SS, 656.3 (M + H), found 656.7. e) Exit of trifluoroacetic acid from [2- (1,1-dioxo-1, 2,3,6-tetrahydro- ^ 6 yopran-4-yl) -4 ^ iperidin-4-yl-phenyl-amide acid 4-cyano-1 H-imidazole-2-carboxylic acid To a solution of the 4- [4-. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3- (1,1-dioxo-1, 2,3,6-tetrahydro- ^ 6-thiopyran-4-yl) -phenyl] -piperidin-1-carboxylic acid (as prepared in the previous step, 81 mg, 0.123 mmoles) in 6 mL of DCM, 0.20 mL of EtOH followed by 2 mL of TFA was added. The resulting solution was stirred at room temperature for 3 hours. Removal of the solvent under reduced pressure afforded 64 mg (96%) of the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz): d 8.02 (s, 1 H), 7.78 (d, 1 H, J = 8.3 Hz), 7.29 (dd, 1 H, J = 8.3, 2.0 Hz), 7.21 (d, 1 H, J = 2.0 Hz), 5.71 (t, 1 H, J = 4.2 Hz), 3.83 (broad s, 2H), 3.51 (d, 2H, J = 12.4 Hz), 3.33 (t, 2H, J = 6.0 Hz), 3.15 (td, 2H, J = 13.1, 2.6 Hz), 3.01 (m, 2H), 2.94 (dddd, 1 H, J = 12.2, 12.2, 3.5, 3.5 Hz), 2.08 (d, 2H, J = 12.9 Hz), 1.91 (m, 2H, J = 13.3, 13.3, 13.3, 3.8 Hz). Mass spectrum (ESI, m / z): calculated for C21 H23N5O3S, 426.2 (M + H), found 426.2.

EXAMPLE 37.sup.4- (1-acetyl-piperidin-4-yl) -2- (1,1-dioxo-1, 2,3,6-tetrahydro-1,6-thiopyran-4-indoin-amide) of 4-cyano-1 H-imidazole-2-carboxylic acid To a suspension of the trifluoroacetic acid salt of [2- (1,1-dioxo-1, 2,3,6-tetrahydro-6-thiopyran-4-yl) -4-p. 4-cyano-1 H-imidazole-2-carboxylic acid penin-4-phenyl] -amide (as prepared in Example 36, step (e), 62 mg, 0.1 15 mmol) in 4 mL of 1: 1 DCM / DMF at room temperature, DIEA (60 μm, 0.345 mmol) was added. The mixture was stirred for 5 minutes, then acetic anhydride (11 pL, 0.121 mmol) was slowly added to the mixture, and the resulting mixture was stirred at room temperature for 0.5 hour. It was treated with 40 mL of EtOAc, the mixture was washed with H20 (2 x 20 mL). The aqueous layers were extracted with EtOAc (4 x 10 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1-4% MeOH / DCM) to give 50.9 mg (95%) of the title compound as a white solid. H NMR (CDCl 3, 400 MHz): d 13.0 (s, 1 H), 9.10 (s, 1 H), 8.13 (d, 1 H, J = 8.4 Hz), 7.77 (d, 1 H, J = 2.3 Hz), 7.26 ( dd, 1H, J = 8.4, 2.0 Hz), 7.08 (d, 1H, J = 2.0 Hz), 5.77 (t, 1H, J = 4.3 Hz), 4.84 (dt., 1H, J = 13.3, 2.1 Hz) , 4.00 (dt, 1H, J = 13.3, 2.1 Hz), 3.89 (broad s, 2H), 3.31 (t, 2H, J = 6.2 Hz), 3.23 (td, 1H, J = 13.2, 2.5 Hz), 3.02 (m, 2H), 2.77 (dddd, 1H, J = 11.9, 11.9, 3.4, 3.4 Hz), 2.68 (ddd, 1H, J = 12.6, 12.6, 2.9 Hz), 2.18 (s, 3H), 1.70-1.97 (m, 4H). Mass spectrum (ESI, m / z): calculated for C23H25N5O4S, 468.2 (M + H), found 468.1.

EXAMPLE 38 { 2-cyclohex-1-eni-f1- (2-dimethylamino-acetyl) -piperidin-4-ill-phenyl > 4-cyano-1H-imidazole-2-carboxylic acid amide A mixture of the trifluoroacetic acid salt of the 4-cyano-H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (as prepared in US Pat. Example 14, step (b), 655 mg, 1.30 mmol) in DCM (15 ml_), cooled to 0 ° C and DIEA (0.92 ml_, 5.2 mmol) was added. Then, dimethylaminoacetyl chloride hydrochloride (21 1 mg, 1.3 mole) was added in portions over 10 minutes. The reaction mixture was stirred at 0 ° C for 30 minutes and allowed to warm to room temperature and stirred for 2 hours. The solvent was removed in vacuo and the resulting residue was partitioned between brine and DCM. The organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified on silica (5% MeOH: DCM), to obtain 432 mg (70%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 9.49 (s, 1 H), 8.24 (d, 1 H, J = 2.3 Hz), 7.70 (s, 1 H), 7.12 (dd, 1 H, J = 8.4, 2.1 Hz), 7.01 (s, 1 H), 5.82 (m, 1 H), 4.75 (d, 1 H, J = 13.4 Hz), 4.13 (d, 1 H, J = 13.4 Hz), 3.57 (d, 1 H, J = 14.2 Hz), 3.18 (d, 1 H, J = 14.2 Hz), 3.12 (td, 1 H, J = 13.3, 2.4 Hz), 2.73 (dddd, 1 H, J = 1 1.9, 1 1.9, 3.8, 3.8 Hz), 2.65 (ddd, 1 H, J = 13.3, 13.3, 2.4 Hz), 2.40 (s, 6H), 2.18-2.32 (m, 4H), 1.60-1.98 (m, 8H). Mass spectrum (ESI, m / z): calculated for C26H32N602l 461.3 (M + H), found 461.2.

EXAMPLE 38b 4-cyano-1 H-imidazole-2- (2-cyclohex-1-enyl-4-f 1 - (2-methylamino-acetyl) -piperidin-4-yn-phenyl) -amide carboxylic Purification by HPLC of Example 38a also provided a small amount of the. { 2-cyclohex-1-enyl-4- [1 - (2-methylamino-acetyl) -piperidin-4-yl] -phenyl} 4-cyano-H-imidazole-2-carboxylic acid amide. H NMR (CD3OD, 400 MHz): d 8.02 (d, 1 H, J = 8.4 Hz), 7.92 (s, 1 H), 7.07 (dd, 1 H, J = 8.4 Hz, J = 2.4 Hz), 6.98 (d, 1 H, J = 2.4 Hz), 5.73-5.68 (m, 1 H), 4.60-4.51 (m, 1 H), 3.76-3.68 (m, 1 H), 3.20-3.1 1 (m, 1 H), 2.81 -2.70 (m, 2H), 2.67 (s, 3H), 2.22-2.13 (m, 4H), 1.88-1.66 (m, 6H), 1.66-1.46 (m, 2H). Mass spectrum (ESI, m / z): calculated for C25H30N6O2, 447.2 (M + H), found 447.3.

EXAMPLE 39 (2-hydroxy-ethyl) -amide of 4-acid. { 4 - [(4-cyano-H-imidazole-2-carbonin-amino-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid a) Salt of trifluoroacetic acid of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide 2-carboxylic To a solution of the 4- (4 { [4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino acid-tert-butyl ester. Cyclohex-1-e piperidine-1-carboxylic acid (as prepared in Example 14, step (a), 81 mg, 0.123 mmol) in 18 mL of DCM, was added 1 mL of EtOH, followed by 5 mL of TFA at 0 ° C. The resulting solution was stirred at room temperature for 0.5 hours, treated with 20 mL of EtOH, followed by 20 mL of n-PrOH and 5 mL of H20, the mixture was then concentrated under reduced pressure to give a slightly yellow solid. Flash chromatography of the compound on silica gel (2-4% MeOH / DCM) gave 0.87 g (85%) of the title compound as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 9.70 (s, 1 H), 9.66 (broad s, 1 H), 9. 15 (s broad, 1 H), 8.29 (d, 1 H, J = 8.3 Hz), 7.78 (s, 1 H), 7.13 (dd, 1 H, J = 8.3, 2.2 Hz), 7.03 (d, 1 H, J = 2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1 H), 3.66 (t, 2H, J = 8.4 Hz), 3.55 (d, 2H, J = 12.3 Hz), 2.95-3.1 1 (m, 2H), 2.76 (m, 1 H), 2.18-2.33 (m, 4H), 1.99-2.15 (m, 4H), 1.82 (m, 4H), 0.97 (t, 2H, J = 8.3 Hz), 0.00 (s, 9H). Mass spectrum (ESI, m / z): calculated for C28H39N5O2YES, 506.3 (M + H), found 506.1. b) 4- (4 { [4-Cyano-1- (2-trimethylsilyl-ethoxymethyl) -1H-imidazole-2-carbonyl-amino) (2-hydroxy-ethyl) -amide 3-cyclohex-1-en-1-phenyl) -piperidin-1-carboxylic acid A solution of the trifluoroacetic acid salt of 4-cyano-1- (2-trimethylsilanyl- (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide ethoxymethyl) -1 H-imidazole-2-carboxylic acid (as prepared in the previous step, 16 mg, 0.192 mmol) and DIEA (134 μ? _, 0.770 mmol) in 4 mL of DCM, was slowly added to a solution of triphosgene (23 mg, 0.0768 mmol) in 4 mL of DCM at -78 ° C under Ar. The mixture was stirred at -78 ° C for 15 minutes, warmed to room temperature and stirred for 15 minutes and cooled to -78 ° C again. A suspension of 2-amino-ethanol (350 pL, 5.77 mmol) in 4 mL of THF was added, and the resulting mixture was warmed to room temperature and stirred for 20 hours under Ar. It was treated with 100 mL of EtOAc, the mixture was washed with H20 (3 x 20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo followed by flash chromatography of the residue on silica gel (10% EtOAc / DCM, then 5% MeOH / DCM), afforded 95 mg (83%) of the title compound as a colorless oil. H NMR (CDCl 3, 400 MHz): d 9.68 (s, 1 H), 8.25 (d, 1 H, J = 8.4 Hz), 7.77 (s, 1 H), 7.12 (dd, 1 H, J = 8.4, 2.2 Hz), 7.01 (d, 1 H, J = 2.2 Hz), 5.94 (s, 2H), 5.83 (m, 1 H), 4.96 (t, 1 H, J = 5.6 Hz), 4.1 1 (d, 2H, J = 13.3 Hz), 3.75 (ddd, 2H, J = 4.4 Hz), 3.66 (t, 2H, J = 8.3 Hz), 3.44 (ddd, 2H, J = 5.0 Hz), 3.36 (t, 1 H , J = 4.6 Hz), 2.91 (ddd, 2H, J = 13.0, 2.2 Hz), 2.66 (dddd, 1 H, J = 12.2, 12.2, 3.3, 3.3 Hz), 2.18-2.33 (m, 4H), 1 .75-1 .91 (m, 6H), 1 .67 (dddd, 2H, J = 12.9, 12.9, 12.9, 4.0 Hz), 0.97 (t, 2H, J = 8.3 Hz), 0.00 (s, 9H) . Mass spectrum (ESI, m / z): calculated for C31 H44N6O4YES, 593.3 (M + H), found 593.1. c) 4- (2-hydroxy-ethyl) -amide. { 4 - [(4-cyano-1 H-imidazole-2-carbonyl) -aminol-3-cyclohex-1-enyl-phenyl) -piperidin-1-carboxylic acid To a solution of 4- (4 { [4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino (2-hydroxy-ethyl) -amide. .3. -3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid (as prepared in the previous step, 95 mg, 0.16 mmol) in 3 mL of DCM, 0.10 mL of EtOH was added followed by 1.0 mL of TFA. The resulting solution was stirred at room temperature for 6 hours. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-8% MeOH / DCM) afforded 68 mg (92%) of the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz): d 8.09 (d, 1 H, J = 8.4 Hz), 8.00 (s, 1 H), 7.15 (dd, 1 H, J = 8.4, 2.2 Hz), 5.79 (m, 1 H), 4.15 (dd, 2H, J = 13.3, 1.1 Hz), 3.61 (t, 2H, J = 5.9 Hz), 3.27-3.32 (m, 2H), 2.90 (ddd, 2H, J = 13.0, 13.0 , 2.5 Hz), 2.73 (dddd, 1 H, J = 12.1, 12.1, 2.6, 2.6 Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J = 12.6, 12.6, 12.6, 4.0 Hz). Mass spectrum (ESI, m / z): calculated for C25H30N6O3, 463.2 (M + H), found 463.2.

EXAMPLE 40 { 4-Cyano-1H-imidazole-2-carboxylic acid 2-cyclohex-1-enyl-4-f 1 - (2-methanesulfonyl-ethyl) -piperidin-4-yl-phenyl) -amide ai Methanesulfonic acid 2-methanesulfonyl ethyl ester To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0 ° C, was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL). , 6.05 mmole) under Ar. The mixture was warmed to room temperature and stirred for 20 hours under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3 x 20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1 H NMR (CDCl 3, 400 MHz): d 4.67 (d, 2 H, J = 5.5 Hz), 3.46 (d, 2 H, J = 5.5 Hz), 3.1 1 (s, 3 H), 3.04 (s, 3 H). b) { 4-cyano-1 H-imidazole-2-carboxylic acid 2-cyclohex-1-enyl-4- [1- (2-methanesulfonyl-etl) -piperidin-4-in-phenyl) -amide To a solution of the trifluoroacetic acid salt of 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (as prepared in Example 14, step (b), 85 mg, 0.174 mmol) and DIEA (91 pL, 0.521 mmol) in 3 mL of DCM at room temperature, the 2-methanesulfonyl-ethyl ester of 2-methanesulfonic acid was added ( as prepared in the previous step, 42 mg, 0.208 mmol). The resulting mixture was stirred at room temperature for 3 hours. It was treated with 50 mL of EtOAc, the mixture was washed with H20 (2 x 20 mL), brine (10 mL) and dried (Na2S04). Removal of the solvent in vacuo followed by flash chromatography of the residue on silica gel (1 -3% MeOH / DCM) afforded 54 mg (65%) of the title compound as a white solid. H NMR (CDCl 3, 400 MHz): d 9.54 (s, 1 H), 8.25 (d, 1 H, J = 8.4 Hz), 7.72 (s, 1 H), 7.15 (dd, 1 H, J = 8.4, 2.0 Hz), 7.04 (d, 1 H, J = 2.0 Hz), 5.85 (m, 1 H), 3.21 (t, 1 H, J = 6.5 Hz), 3.09 (s, 3H), 3.02-3.1 1 ( m, 2H), 2.92 (t, 2H, J = 6.5 Hz), 2.52 (dddd, 1 H, J = 12.1, 12.1, 3.3, 3.3 Hz), 2.18-2.34 (m, 4H), 2.18 (t, 2H, J = 10.8 Hz), 1.64-1.94 (m , 8H). Mass spectrum (ESI, m / z): calculated for C25H31 N5O3S, 482.2 (M + H), found 482.2. The following compounds have been prepared according to the examples as indicated: Spectrum structure of mmaassaass, _. . , _,. Proc. of the Example ",,?, * Found Formula. [[MM ++ HH]] + Calculated Example 497. 2 497.2 C28H28N603 29 497. 2 497.3 C28H28N603 29 EXAMPLE 43 { 2-cyclohex-1-enyl-4-G? - (pyridine-3-carbonyl) -piperidin-4-in-phenyl} 4-cyano-1 H-imidazole-2-carboxylic acid amide A solution of the trifluoroacetic acid salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (as prepared in Example 14, step (b), 75.0 mg, 0.15 mmole) in CH2Cl2 (10 mL), treated with Et3N (64.1 μ? _, 0.46 mmol) and cooled to 0 ° C. The mixture was treated with nicotinoyl chloride hydrochloride (0.030 g, 0.17 mmol) and stirred at 0 ° C for 15 minutes, then at room temperature for 17 hours. The reaction mixture was adsorbed directly on silica gel. Chromatography on silica gel afforded (10% MeOH in EtOAc) of the title compound (61.0 mg, 83%) as a white solid. 1 H NMR (CDCl 3; 400 MHz): d 9.51 (broad s, 1 H), 8.77 (s, 1 H), 8.70-8.66 (m, 1 H), 8.32 (d, 1 H, J = 8.4 Hz), 7.86-7.81 (m , 1 H), 7.70 (s, 1 H), 7. 42-7.37 (m, 1 H), 7.17 (d, 1 H, J = 8.4 Hz), 7.06-7.04 (m, 1 H), 5.87-5.82 (m, 1 H), 4.98-4.87 (m, 1 H), 3.94-3.84 (m, 1 H), 3.29-3.18 (m, 1 H), 2.98-2.86 (m, 1 H), 2.86-2.76 (m, 1 H), 2.34-2.20 (m, 4H) ), 1.94-1.72 (m, 9H). LC-MS (ESI, m / z): calculated for C28H28N6O2, 481.2 (M + H), found 481.3.

EXAMPLE 44 Salt of trifluoroacetic acid from (2-cyclohex-1-enyl-4-. {1-r2- (2-hydroxy-ethylamino) -acet-n-pyridin-4-yl-phenyl) 4-cyano-1H-imidazole-2-carboxylic acid amide a) [2- (4-. {4 - [(4-Cyano-1 H-imidazole-2-carbonyl) -amino-3-cyclohex-1-enyl-phenyl) -s-butyl ester piperidin-1-yl) -2-oxo-ethylVcarbamic A solution of N-BOC-glycine (0.29 g, 1.63 mmol) in CH2Cl2 (10 mL) was treated with DIEA (0.85 mL, 4.90 mmol), HOBt (0.26 g, 1.96 mmol) and EDCI (0.38 g, 1.96 mmol). The mixture was stirred at room temperature for 10 minutes and added to a suspension of the trifluoroacetic acid salt of 4-cyano (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide. -1H-imidazole-2-carboxylic acid (as prepared in Example 14, step (b), 0.80 g, 1.63 mmol) in CH2Cl2 (20 mL). The solution was stirred at room temperature for 17 hours. The solvents were evaporated in vacuo. Chromatography on silica gel (50% EtOAc in hexanes) provided the title compound (0.41 g, 47%) as a white solid. 1 H NMR (CDC, 400 MHz): d 9.53 (s, 1 H), 8.26 (d, 1 H, J = 8.4 Hz), 7.80-7.78 (m, 1 H), 7.71 (s, 1 H), 7.45-7.43 (m, 1 H), 7.06 (d, 1 H, J = 8.4 Hz), 7.00 (s, 1 H) ), 5.83 (broad s, 1 H), 5.76 (broad s, 1 H), 4.78-4.68 (m, 1 H), 3.96-3.85 (m, 2H), 3.17-3.03 (m, 1 H), 2.78 -2.63 (m, 2H), 2.29 (broad s, 2H), 2. 22 (broad s, 2H), 1 .95-1.87 (m, 2H), 1.86-1 .72 (m, 4H), 1 .70-1.55 (m, 2H), 1.44 (s, 9H). LC-MS (ESI, m / z): calculated for C 29 H 36 6 O 4 533.3 (M + H), found 532.9. b) Trifluoroacetic acid salt of 4- (1- (2-amino-acetyl) -pperidin-4-yn-2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1 H acid -imidazole-2-carboxylic acid A solution of [2- (4-. {4 - [(4-cyano-1 H-midazole-2-carbonyl) -amino] -3-cyclohex-1-phenyl-phenyl ester} -piperidin-1-yl) -2-oxo-ethyl] -carbamic acid (as prepared in the previous step, 0.41 g, 0.77 mmol) in CH2Cl2 (20 ml_), treated with EtOH (0.2 mL) and TFA (6 mt_). The mixture was stirred at room temperature for 45 minutes and the solvents were evaporated in vacuo. The raw material was used directly in the next step. LC-MS (ESI, m / z): calcd for C 24 H 28 N 6 O 2 433.2 (M + H), found 433.2. c) Trifluoroacetic acid salt of 4- (1-cyclohex-1-enyl-4- (1 - [2- (2-hydroxy-ethylamino) -acetyl-piperidin-4-yl) -phenyl) -amide. cyano-1 H-imidazole-2-carboxylic A suspension of the trifluoroacetic acid salt of the. { 4-cyano-1 H-imidazole-2-carboxylic acid 4- [1 - (2-amino-acetyl) -piperidin-4-yl] -2-cyclohex-1-enyl-phenyl] -amide (as prepared in the previous step, 0.42 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with Na (OAc) 3BH (0.33 g, 1.54 mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture was stirred at room temperature for 1 hour and the solvent was vaporized in vacuo. The residue was taken up in MeOH and the solids filtered, and the filtrate was concentrated in vacuo. Reverse phase HPLC (column C-18) (20% to 60% acetonitrile in water with 0.1% TFA for 30 minutes), gave the title compound (83 mg, 19% over two steps) as a white solid . H NMR (CD3OD, 400 MHz): d 8.16-8.09 (m, 1 H), 8.05-8.01 (m, 1 H), 7.22-7.15 (m, 1 H), 7.1 1 -7.06 (m, 1 H) , 5.84-5.79 (m, 1 H), 4.72-4.62 (m, 1 H), 4.24-3.91 (m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92- 2.79 (m, 2H), 2.28 (broad s, 4H), 1 .98-1.89 (m, 2H), 1 .89-1.76 (m, 4H), 1 .76-1 .57 (m, 2H). LC-MS (ESI, m / z): calculated for C 26 H 32 N 6 O 3 477.2 (M + H), found 477.2.

EXAMPLE 45 Salt of trifluoroacetic acid from (2-cyclohex-1-enyl-4-f1-r2- (2-hydroxy-ethyl) -methyl-amino-acetyl-piperidin-4-yl-phenyl) -am 4-cyano-1H-imidazole-2-carboxylic acid A solution of the trifluoroacetic acid salt of (2-cyclohex-1-enyl-4-. {1 - [2- (2-hydroxy-ethylamino) -acetyl] -piperidin-4-yl}. ) - 4-cyano-1 H-imidazole-2-carboxylic acid amide (as prepared in Example 44, step (c), 50.0 mg, 0.085 mmol) in MeOH (3 mL), treated with Na (OAc) ) 3BH (39.5 mg, 0.19 mmol) and 37% aqueous formaldehyde (8.2 μm, 0.10 mmol). The mixture was stirred at room temperature for 5.5 hours and the solvents were removed in vacuo. Reverse phase HPLC (column C-18) (10% to 50% of acetonitrile in water with 0.1% TFA for 30 minutes), gave the title compound (19.5 mg, 47%) as a white solid. H NMR (CD3OD, 400 MHz): d 8.12 (d, 1H, J = 8.4 Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J = 8.4, 2.0 Hz), 7.09 (d, 1H, J = 2.0 Hz), 5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 2.32-2.24 (m, 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m , 2H). LC-MS (ESI, miz): calculated for C27H34N6O3491.3 (M + H), found 491.2.

EXAMPLE 46 Salt of trifluoroacetic acid of r4- (1-acetyl-piperidin-4-yl) -2 - (1,2,5,6-tetrahydro-pyridin-3-yl) -phenyl] -amide of acid 4-cyano-1H-imidazole-2-carboxylic acid a) 5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A solution of LDA (23.4 mL, 35.1 mmol, 1.5 M in cyclohex) in THF (50 mL) was cooled to -78 ° C under Ar. The solution was treated with the tert-butyl ester of 3-oxo-piperidin-1-carboxylic acid (5.00 g, 25.1 mmol) as a solution in THF (15 mL) via dropwise addition, and stirred for 15 minutes. . The mixture was treated with 1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl) sulfonyl] methanesulfonimide (12.5 g, 35.1 mmol) as a solution in THF (40 mL). The mixture was allowed to warm to room temperature and stirred 2.5 hours. The reaction was quenched with saturated aqueous NaHCO3, diluted with Et2O and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel (5% EtOAc in hexanes) afforded the title compound (2.45 g, 30%) as a colorless oil. H NMR (CDCl 3, 400 MHz): d 5.97-5.89 (m, 1 H), 4.09-4.01 (m, 2H), 3.54-3.45 (m, 2H), 2.36-2.26 (m, 2H), 1.48 (s, 9H). LC- S (ESI, m / z): calculated for C11H16F3N05S 332.1 (M + H), found 332.1. b) 5- (4,4,5,5-Tetramethyl-f 1, 3,2ldioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester PdCI2dppf (0.16 g, 0.22 mmole), KOAc (2.18 g, 22.2 mmole), 4,4,5l5,4 ', 4', 5 ', 5'-octamethyl- [2.2'] bi [[1 , 3,2] dioxaborolanyl] (2.07 g, 8.13 mmol) and dppf (0.12 g, 0.22 mmol) in a round bottom flask, and the flask was rinsed abundantly with Ar. A degassed solution of the 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated at 80 ° C for 16 hours. The mixture was filtered through a glass frit funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Chromatography on silica gel (5% EtOAc in hexanes) afforded the title compound (1.62 g, 71%) as a colorless oil. 1 H NMR (CDCl 3, 400 MHz): d 6.69-6.60 (m, 1 H), 3.98 (broad s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 ( s, 9H), 1.27 (s, 12H). LC-MS (ESI, m / z): calculated for C18H28BN04 310.2 (M + H), found 31 1.0. c) 4- (4-Nitro-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester The title compound was prepared by the Suzuki coupling procedure of Example 35, step (b), using 4-nitrophenylboronic acid (167 mg, 1.00 mmol) and 4-trifluoromethanesulfonyloxy-3,6-dihydro-tert-butyl ester. -2H-pyridine-1-carboxylic acid (as prepared in Example 13, step (a), 295 mg, 1.00 mmol). Chromatography on silica gel (10% EtOAc in hexanes) provided the title compound (273 mg, 90%) as an oil. 1 H NMR (CDCl 3, 400 MHz): d 8.19 (d, 2 H, J = 8.8 Hz), 7.50 (d, 2H, J = 8.8 Hz), 6.23 (m, 1 H), 4.12 (m, 2H), 3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H). d) 1 -f4- (4-Amino-phenyl) -piperidin-1-yl-1-ethanone A solution of 4- (4-nitro-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 304 mg, LOO mmol) in a mixture 1: 1 DCM / TFA (10 mL) was stirred at room temperature for 3 hours and concentrated. The residue was dried in vacuo overnight, taken up in CH 2 Cl 2 (10 mL) and cooled to 0 ° C. Et3N (280 pL, 2 mmol) was added dropwise to this solution, followed by acetic anhydride (102 pL, 1 mmol). The resulting mixture was stirred at 0 ° C for 1 hour and allowed to warm to room temperature. The reaction mixture was washed with brine and the organic layer was separated, dried and concentrated. The resulting product was reduced to obtain the title compound (143 mg, 65%), using a procedure similar to Example 4, step (d). H NMR (CDCl 3, 400 MHz): d 6.97 (d, 2H, J = 8.4 Hz), 6.64 (d, 2H, J = 8.4 Hz), 4.75 (m, 1 H), 3.93 (m, 1 H), 3.13 (m, 3H), 2.66 (m, 2H), 2.12 (s, 3H), 1.84 (m, 2H) ), 1.57 (m, 2H). §1 1 - [4- (4-Amino-3-bromo-phenyl) -piperidin-1-yl] -ethanone A solution of 1 - [4- (4-amino-phenyl) -piperidin-1-yl] -ethanone (as prepared in the previous step, 0.36 g, 1.66 mmole) in CH2Cl2 (10 ml_), was cooled to - 78 ° C and treated with NBS (0.28 g, 1.58 mmoies) as a suspension in CH2Cl2 (4 ml_). The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO and concentrated in vacuo. The raw material was used directly in the next reaction. LC-MS (ESI, miz): calculated for C13H17BrN20 297.1 (M + H), found 297.1. f) 5-f5- (1-Acetyl-piperidin-4-yl) -2-amino-phenyl-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester A solution of 5- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( as prepared in Example 46, step (b), 0.62 g, 2.02 mmoies) and 1 - [4- (4-amino-3-bromo-phenyl) -piperidin-1-yl] -ethanone (as prepared in the previous step, 0.20 g, 0.67 mmoles) in toluene: EtOH (2: 1, 9 mL), treated with aqueous 2.0 Na2CO3 (2.7 mL, 5.38 mmol), and degassed with sonication under Ar. The mixture was heated to 80 ° C, treated with Pd (PPh3) 4 (54 mg, 0.05 mmol) and stirred at 80 ° C for 4.5 hours. The reaction was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (0.25 g, 93%) as a white off-white solid. LC-MS (ESI, m / z): calculated for C23H33N303 422.2 (M + Na), found 422.0. g) 5- (5- (1-Acetyl-piperidin-4-yl) -2- (f4-cyano-1 - (2-tritymethylsilanyl-ethoxymethyl) -1H-imidazole-2-tert-butyl ester. -carbonyl-amino) -phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid A solution of the 5- [5- (1-acetyl-piperidin-4-yl) -2-amino-phenyl] -3,6-dihydro-2H-pyridine-1-carboxylic acid tert -butyl ester (as prepared in the previous step, 0.25 g, 0.63 mmol) in CH2Cl2 was treated with PyBroP (0.44 g, 0.94 mmol) and potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in Example 3, step (d), 0.21 g, 0.69 mmol). The resulting suspension was cooled to 0 ° C and treated with DIEA (0.33 ml_, 1.88 mmol). The ice bath was removed and the mixture was stirred at room temperature for 18 hours. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel (25-45% EtOAc in hexanes, then 100% EtOAc) afforded the title compound (399 mg, 98%) as a white solid. LC-MS (ESI, m / z): calculated for C34H48N6O5Si 649.4 (M + H), found 649.9. h) Exit of trifluoroacetic acid from [4- (1-acetyl-piperidin-4-yl] -d ^^^ - tetrahydro-pyridin-S-iO-phenyl-amide of 4-cyano-1 H-imidazole- 2-carboxylic A solution of 5- (5- (1-acetyl-piperidin-4H'l) -2- { [4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imida-2-tert-butyl ester. -2-car ^ amino.}. Phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid (as prepared in the previous step, 0.40 g, 0.61 mmol) in CH2Cl2 (20 ml_) and EtOH ( 0.4 ml_), was treated with TFA (3 mL). The solution was stirred at room temperature for 0.5 hours. The solvents were evaporated in vacuo and the residue taken immediately in EtOH (25 mL) and stored at 5 ° C for 11 hours. The solution was concentrated in vacuo and the residue was taken up in CH2Cl2 (20 mL) and EtOH (0.4 mL), then treated with TFA (6 mL). The reaction was stirred at room temperature for 2 hours and the solvents were evaporated in vacuo. Reverse phase HPLC (column C-18) (10 to 80% acetonitrile in water with 0.1% TFA for 30 minutes) afforded the title compound (56.9 mg, 22%) as a white solid. 1 H NMR (CDCl 3, 400 MHz): d 8.06 (s, 1 H), 7.81 (d, 1 H, J = 8.4 Hz), 7.32 (d, 1 H, J = 8.4 Hz), 7.22 (s, 1 H ), 6.10-6.03 (m, 1 H), 4.74-4.64 (m, 2H), 4.1 1 -4.02 (m, 1 H), 3.95 (s, 2H), 3.50-3.37 (m, 2H), 3.29- 3.20 (m, 1 H), 2.93-2.82 (m, 1 H), 2.80-2.69 (m, 1 H), 2.62-2.53 (m, 2H), 2.16 (s, 3H), 1 .98-1. 84 (m, 2H), 1.78-1.54 (m, 2H). LC-MS (ESI, m / z): calculated for C23H26N6O2 419.2 (M + H), found 419.2.

EXAMPLE 47 Salt of (4- (4 - [(4-cyano-1H-imidazole-2-carbonyl) -aminol-3-cyclohex-1-enyl-pheny1) -piperidin-1-yl acid trifluoroacetic acid) -acetic A flask was charged with the TFA salt of the (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide of 4-cyano-1 H -amidazole-2-acid. carboxylic (33 mg, 0.067 mmol) (as prepared in Example 14, step (b)), t-butyl bromoacetate (10 μ? _, 0.067 mmol), NEt3 (20 pL, 0.135 mmol) and 0.25 mL of DCM and was stirred for 10 hours at 25 ° C. The reaction mixture was loaded into a 5 g SPE cartridge (silica gel) and 23 mg (70%) of the (4- {4 - [(4-cyano-1 H-imidazole) tert-butyl ester. -2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl.} - piperidin-1-yl) -acetic was eluted with 25% EtOAc / DCM. This compound was dissolved in 1 mL of DCM and 20 pL of EtOH and 1 mL of TFA was added, and the reaction was stirred for 3 hours at 25 ° C. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% of TFA / H20 for 12 minutes, to provide 10 mg (40%) of a white solid. 1 H NMR (400 MHz, CD 3 OD): d 8.16 (d, 1 H), 8.02 (s, 1 H), 7.22 (dd, 1 H), 7.10 (d, 1 H), 5.72 (m, 1 H), 4.04. (s, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1 H), 2.29 (m, 4H), 2.10 (m, 4H), 1.82 (m, 4H). Mass spectrum (ESI, m / z): calculated for C 24 H 27 N 5 O 3, 434.2 (M + H), found 434.2.

EXAMPLE 48 Salt of trifluoroacetic acid from 4-cyano-1H (4-H- (3-amino-3-methyl-butyryl) -piperidin-4-yn-2-cyclohex-1-enyl-phenyl) -amide - imidazole-2-carboxylic acid a) [3- (4- {4 - [(4-cyano-1 H-imidazole-2-carbonyl) -amino-3-cyclohex-1-enyl-phenyl) -piperidine- tert -butyl ester 1 -yl) -1, 1 -dimethyl-3-oxo-propyl-carbamic A mixture of the trifluoroacetic acid salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (as prepared in Example 14, step (b), 40.0 mg, 0.0818 mmole), 3-tert-butoxycarbonylamino-3-methyl-butyric acid (J. Med. Chem., 34 (2), 633-642, (1991), 21.4 mg, 0.0981 mmol) and PyBroP (55.0 mg, 0.0981 mmol) in dichloroethane (2 mL), was added to DIEA (43 pL, 0.25 mmol), and the resulting mixture was stirred at room temperature for 1 day under Ar. The mixture was diluted with EtOAc (30 mL) and washed with H20 (2 x 10 mL), brine (10 mL), dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10-40% EtOAc / hexane) to provide 33.0 mg (70%) of the title compound as a colorless oil. Mass spectrum (ESI, m / z): calculated for C32H42N604, 575.3 (M + H), found 574.8. b) Salt of trifluoroacetic acid of. { 4-cyano-1 Hi m idazo l-2 4- [1- (3-amino-3-methyl-butyryl) -piperidin-4-yn-2-cyclohex-1-enyl-phenyl) -amide -carboxylic To a solution of [3- (4-. {4 - [(4-cyano-H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl] -butyl ester. . -piperidin-1 -yl) -, 1-dimethyl-3-oxo-propyl] -carbamic acid (33.0 mg, 0.0574 mmol) (as prepared in the previous step) in 3 mL of DCM and 0.10 mL EtOH at 0 ° C, 1.0 mL of TFA was added, the mixture was warmed to room temperature and stirred for 3 hours. The reaction was diluted with 3 mL of n-PrOH and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 3-8% MeOH / DCM) to provide 33.5 mg (99%) of the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3): d 13.3 (s, 1 H), 9.52 (s, 1 H), 8.57 (broad s, 3H), 8.26 (d, 1 H, J = 8.6 Hz), 7.69 (s) , 1 H), 7.02 (dd, 1 H, J = 8.6, 1.7 Hz), 6.98 (d, 1 H, J = 1.7 Hz), 5.78 (m, 1 H), 4.67 (br d, 1 H, J = 13.4 Hz), 3.88 (br d, 1 H, J = 13.4 Hz), 3.10 (m, 1 H), 2.55-2.85 (m, 4H), 2.23 (m, 4H), 1. 72-2.01 (m, 8H), 1.50 (s, 6H). Mass spectrum (ESI, m / z): calculated for C27H34N602, 475.3 (M + H), found 475.1.

EXAMPLE 49 Salt of bis-trifluoroacetic acid of 4H- [1,2,41-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide Methyl ester of 1- (2-trimethylsilanyl-ethoxymethyl) -1 H- [1, 2,4l-triazole-3-carboxylic acid \ / Yes, and \ To a suspension of NaH (60% dispersion) (200 mg, 5.00 mmoles) in DMF (5 mL) at 0 ° C, a solution of methyl-1 H-1, 2,4-triazolecarboxylate (635 mg, 5.00 mmol) in DMF (5 mL) was added dropwise. The The resulting suspension was stirred at the same temperature for 30 minutes and treated with SEMCI (0.90 mL, 5.0 mmol). The resulting solution was stirred at room temperature for 30 minutes and poured into ice. The product was extracted with ether (3 x 20 mL). The ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc / hexane) to obtain the title compound (530 mg, 41%). Mass spectrum (ESI, miz): calculated for dohhgNaOaSi, 258.1 (M + H), found 258.2. b) 4- (3-cyclohex-1-enyl-4-. {[1- (2-trimethylalanyl-ethoxymethyl) -1 H- [1, 2,4-ltriazole-3] -butyl ester. -carbonyl-amino) -phenyl) -piperidine-1-carboxylic acid To a solution of 1- (2-trimethylsilanyl-ethoxymethyl) -1 H- [1, 2,4] -triazole-3-carboxylic acid methyl ester (as prepared in the previous step, 257 mg, 1.00 mmol) in EtOH (2 mL), 2N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at room temperature for 20 minutes. minutes and concentrated in vacuo. The residue obtained was suspended in ether (10 ml_) and subjected to sonication for 5 minutes. The ether was then removed in vacuo and the resulting residue was dried for 4 hours to obtain the potassium salt of 1- (2-trimethylsilyl-ethoxymethyl) -1 H- [1, 2,4] -triazole-3-acid. carboxylic (273 mg, 97%), which was used directly in the next step without any additional purification. A mixture of the potassium salt of 1- (2-trimethylsilanyl-ethoxymethyl) -H- [1, 2,4] -triazole-3-carboxylic acid (as prepared above, 28 mg, 0.10 mmol), DIEA (34 pL, 0.20 mmole), 4- (4-amino-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg, 0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL), was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO 3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The product was chromatographed on silica (20-40% EtOAc / hexane) to obtain the title compound (31.9 mg, 55%). Mass spectrum (ESI, m / z): calculated for C3iH47N504Si, 481.2 (M-BOC + 2H), found 481.2. c) Bis-trifluoroacetic acid salt of 4H- [1,4,4-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide) To a solution of 4- (3-cyclohex-1-enyl-4 [1- (2-trimethylsilanyl-ethoxymethyl) -H- [1, 2,4] -triazole-3-carbonyl] - tert-butyl ester aminoHeni piperidin-1 -carboxylic acid (as prepared in the previous step, 81.9 mg, 0.140 mmol) in DCM (0.4 ml_) and EtOH (13 μ? _), was added TFA (0.13 ml_) .The resulting solution was stirred at room temperature for 3 hours and concentrated in vacuo.The obtained residue was dried under vacuum for 1 hour, suspended in ether (10 mL) and sonicated for 5 minutes The solid formed was collected by suction filtration Obtain the title compound (56 mg, 68%). 1 H NMR (CD3OD, 400 MHz): d 8.53 (broad s, 1 H), 8.20 (d, 1 H, J = 8.4 Hz), 7.21 (dd, 1 H, J = 8.4, 2.1 Hz), 7.1 1 (d, 1 H, J = 2.1 Hz), 5.83 (s broad, 1 H), 3.45 (m, 2 H), 3.19 (m, 2 H), 2.98 (m , 1 H), 2.28 (m, 4H), 2.14 (m, 2H) and 1.95-1.75 (m, 6H) Mass spectrum (ESI, m / z): calculated for C2oH25N5O, 352.4 (M + H), found 352.2.

EXAMPLE 50 Salt of trifluoroacetic acid of 5-chloro-4H- [1,2,41-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-phenyleuroamide) a) 5-Chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-f 1, 2,41-triazole-3-carboxylic acid methyl ester To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5 mL) at 0 ° C, a solution of 5-chloro-1 H- methyl ester was added dropwise. [1, 2,4] -triazole-3-carboxylic acid (Bull. Pharm. Sci., 20 (1): 47-61, (1997), 218 mg, 1.35 mmol) in DMF (10 mL). The resulting suspension was stirred at the same temperature for 30 minutes and then treated with SEMCI (0.24 mL, 1.4 mmol). The resulting solution was stirred at room temperature for 30 minutes and poured on ice. The mixture was extracted with ether (3 x 20 mL), and the ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc / hexane) to obtain the title compound (227 mg, 58%). Mass spectrum (ESI, m / z): calculated for C10H18CIN3O3Si, 292.0 and 294.0 (M + H), found 291.5 and 293.6. b) 4- (4. {[[5-Chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1 H- [1,4] -triazole-3-carbonyl ester amino) -3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid To a solution of 4- (4. {[[5-chloro-1- (2-trimethylsilyl-ethoxymethyl) -1 H- [1, 2,4] triazole-3-methyl ester -carboxylic acid (as prepared in the previous step, 227 mg, 0.780 mmol) in EtOH (2 mL), was added 2N KOH (0.4 mL, 0.8 mmol) .The resulting solution was stirred at room temperature for 20 minutes and The residue obtained was concentrated in vacuo. suspended in ether (10 ml_) and sonicated for 5 minutes. The ether was then removed and the resulting residue was dried in vacuo for 4 hours to obtain the potassium salt of 4- (4. {[[5-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1 H - [1, 2,4] triazole-3-carboxylic acid (223 mg, 91%), which was used directly in the next step without further purification A mixture of the potassium salt of 4- (4-. . [5-Chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1 H- [1, 2,4] -triazole-3-carboxylic acid (as prepared above, 35 mg, 0.10 mmol), DIEA (34 pl_, 0.10 mmoles), 4- (4-amino-3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg, 0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirred at room temperature for 12 hours, the reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO3 (10 mL). and water (10 ml_) .The organic layer was separated, dried (Na 2 SO 4) and concentrated in vacuo. was chromatographed on silica (20-40% EtOAc / hexane) to obtain the title compound (52 mg, 85%). 1 H NMR (CDCl 3, 400 MHz): d 9.60 (s, 1 H), 8.29 (d, 1 H, J = 8.4 Hz), 7.18 (dd, 1 H, J = 8.4, 2.2 Hz), 7.13 (d, 1 H, J = 2.2 Hz), 5.99 (s, 2H), 5.84 (broad s, 1 H), 4.18-4.25 (m, 2H), 3.72-3.76 (m, 2H), 2.58-2.67 (m, 2H) ), 2.51-2.64 (m, 1 H), 2.18-2.33 (m, 4H), 1.78-1.92 (m, 6H), 1.55-1.65 (m, 2H), 1.49 (s, 9H), 0.93- 0.98 (m, 2H), 0.10 (s, 9H).

Trifluoroacetic acid salt of 5-chloro-1 H- [1, 2,4-l-triazole-3- (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide) carboxylic To a solution of 4- (4. {[[5-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1 H- [1, 2,4] -triazole-3-carbonyl] -butyl ester -amino.} - 3-cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid (as prepared in the previous step, 63.3 mg, 0. 102 mmol) in DCM (0.5 ml_) and EtOH (1 1 pl_), TFA (0.1 mL) was added.

After stirring the resulting mixture at room temperature for 12 hours, another 0.1 mL of TFA was added. The reaction mixture was stirred for an additional 5 hours at room temperature, the solvents were evaporated and the title compound was purified by RP-HPLC (C18) eluting with 20-70% CH3CN in 0.1% TFA / H2O for 20 minutes. to obtain the title compound (30 mg, 58%). H NMR (CD3OD, 400 MHz): d 8.14 (d, 1 H, J = 8.4 Hz), 7.20 (dd) 1 H, J = 8.4, 2.1 Hz), 7.13 (d, 1 H, J = 2.1 Hz), 5.82 (broad s, 1 H), 3.45 (m, 2 H), 3.19 (m, 2 H), 2.98 (m , 1 H), 2.28 (m, 4H), 2.14 (m, 2H) and 1.95-1.75 (m, 6H). Mass spectrum (ESI, m / z): calculated for C20H24CIN5O, 386.1 and 388.1 (+ H), found 386.2 and 388.1.

EXAMPLE 51 Exit of bis-trifluoroacetic acid from [2-cyclohex-1-enyl-4- (cis-2,6-dimethyl-piperidin-4-yl) -phenin-amide of 5-cyano-1 H-imidazole- 2-carboxylic acid and bis-trifluoroacetic acid salt of 5-cyano [2-cyclohex-1-enyl-4- (trans-2,6-dimethyl-p-peridin-4-yl) -phenyl-1-amide] -1H- imidazole-2-carboxylic acid a) Ter-Butyl Ester of cis / trans 2,6-dimethyl-4-oxo-piperidin-1-carboxylic acid A solution of cis / trans-2,6-dimethylpiperidinone (Coll. Czech, Chem. Commun .: 31 (11), 4432-41, (1966), 1.27 g, 10.0 mmol) in ether (100 mL ), treated with 1 N aqueous NaOH (11 mL, 11 mmol) and (BOC) 20 (2.18 g, 10.0 mmol). The resulting mixture was stirred at room temperature during 48 hours. The ether layer was separated, dried and concentrated. The residue was chromatographed on silica (10% EtOAc-hexane) to obtain the title compound (1.10 g, 50%): LC-MS (ESI, m / z): calculated for C12H2i N03, 128.1 ( M-BOC + 2H), found 128.1. b) 4- (4-Amino-phenyl) -cis / trans 2,6-dimethyl-piperidin-1-carboxylic acid tert-butyl ester A solution of the cis / trans N-Boc-2,6-dimethylpiperidinone (as prepared in the previous step, 1.14 g, 5.00 mmol) in THF (20 mL), was cooled to -78 ° C and treated with LDA (1.5 M solution in cyclohex, THF and ethylbenzene, 4.4 mL, 6.5 mmol) under Ar. The resulting mixture was stirred at the same temperature for 30 minutes and treated with N-phenyltrifluoromethanesulfonimide (2.34 g, 6.55 mmol) in THF (20 mL). The reaction mixture was stirred for another 30 minutes and allowed to warm to room temperature. After 30 minutes at room temperature, the reaction mixture was concentrated in vacuo and the residue taken up in ether (20 mL) and washed with cold water (2 10 mL). The ether layer was dried (Na2SO4) and concentrated to give the tert-butyl ester of cis / trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid (890 mg, 49%) which was used directly in the next step. The title compound was then prepared according to the Suzuki coupling procedure of Example 35, step (b), using 4-aminophenylboronic acid (219 mg, 1.00 mmol) and cis / trans-tert-butyl ester. -2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid (as prepared above, 321 mg, 1.00 mmol). Chromatography on silica gel (10-20% EtOAc / hexanes) gave the 4- (4-amino-phenyl) -2,6-dimethyl-3,6-dihydro-2H-pyridine-tert-butyl ester. 1-carboxylic (172 mg, 57%): Mass spectrum (ESI, m / z): calculated for Ci8H26N202, 303.2 (M + H) found 303.1. A solution of 4- (4-amino-phenyl) -2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared above, 380 mg, 1.25 mmol) in MeOH (10 mL) was subjected to hydrogenation over 10% Pd / C (190 mg) at 1,406 kgf / cm2 (20 psi) for 1 hour. The solution was filtered through a pad of Celite, and concentrated to provide the title compound (360 mg, 94%). Mass spectrum (ESI, m / z): calculated for C18H28N2O2, 305.2 (M + H), found 305.6. c) 4- (4-Amino-3-cyclohex-1-enyl-phenyl) -cis / trans 2,6-dimethyl-piperidin-1-carboxylic acid tert-butyl ester To a solution of the 4- (4-amino-phenyl) -2,6-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 334 mg, 1.09 mmol) in DCM (10 mg). mL) was added NBS (195 mg, 1.09 mmol) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to obtain the 4- (4-amino-3-bromo-phenyl) -cis / trans-2,6-dimethyl-piperidin tert-butyl ester. -1-carboxylic acid (367 mg, 87%). Mass spectrum (ESI, m / z): calculated for Ci8H27BrN2O2, 327.0 and 329.0 (M-t-Bu + H), found 327.0 and 328.9. The title compound was then prepared according to the Suzuki coupling procedure of Example 12, step (d) using cyclohexane-1-enyl boronic acid (157 mg, 1.25 mmol) and the tert-butyl ester of 4-hydroxybenzoate. - (4-amino-3-bromo-phenyl) -2,6-dimethyl-piperidin-1- carboxylic acid (as prepared above, 382 mg, 1 .00 mmol) and subjected to chromatography on silica (20% EtOAc / hexanes) to provide 254 mg (66%). Mass spectrum (ESI, m / z): calculated for C 24 H 36 N 2 O 2, 384.2 (M + H), found 385.1. d) 4- (4- { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl-amino) -3-cyclohex-1-enyl-tert-butyl ester phenyl) -cis-2,6-dimethyl-piperidin-1-carboxylic acid; and 4- (4- { [4-Cyano-1- (2-trifatyl-silanyl-ethoxymethyl) -1H-imidazole-2-carbonin-amino) -butyl ester 3-cyclohex-1-enyl-phenyl) -trans-2,6-dimethyl-piperidin-1-carboxylic acid A mixture of the potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in Example 3, step (d), 384 mg, 1.00 mmol ), DIEA (0.34 μ? _, 2.0 mmoles), 4- (4-amino-3-cyclohex-1-enyl-phenyl) -2,6-dimethyl-piperidin-1-carboxylic acid tert-butyl ester (as was prepared in the previous step, 384 mg, 1 .00 mmol) and PyBroP (699 mg, 1.50 mmol) in DCM (20 mL), was stirred at room temperature. environment for 12 hours. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to obtain a mixture of the two above title compounds (321 mg, 50.7%). The mixture was chromatographed on silica (10-20% EtOAc / hexane) to obtain the individual title compounds. 4- (4. {[4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3-cyclohex-1-tert-butyl ester. enyl-phenyl) -trans-2,6-dimethyl-piperidin-1-carboxylic acid (31 mg). Mass spectrum (ESI, m / z): calculated for C35H5iN504Si, 634.3 (M + H), found 634.1. 4- (4. {[4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3-cyclohex-1-tert-butyl ester. enyl-phenyl) -cis-2,6-dimethyl-piperidin-1-carboxylic acid contaminated with 10% of the 4- (4. {4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -butyl ester. ) -1 H-imidazole-2-carbonyl] -amino.} - 3-cyclohex-1-enyl-phenyl] -trans-2,6-dimethyl-piperidin-1-carboxylic acid (290 mg). Mass spectrum (ESI, m / z): calculated for C35H51N504Si, 634.3 (M + H), found 634.1. e) Bis-trifluoroacetic acid salt of 5-cyano-1 [2-cyclohex-1-enyl-4- (cs-2,6-dimethyl-piperidin-4-yl) -phenyl-amide] H-imidazole-2-carboxylic acid and bis-trifluoroacetic acid salt of 5-cyano [2-cyclohex-1-enyl-4- (trans-2,6-dimethyl-piperidin-4-yl) -phenyl-amide] -1 H-imidazole-2-carboxylic acid The title compounds were prepared from 290 mg (0.457 mmol) of the 4- (4. {4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-tert-butyl ester. 2-carbonyl] -amino.} - 3-cyclohex-1-enyl-phenyl) -cis-2,6-dimethyl-piperidine-1-carboxylic acid and 31 mg (0.048 mmol) of the 4- tert-butyl ester (4- { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -imidazole-2-carbonyl] -amino.} - 3-cyclohex-1-enyl-phenyl) -trans-2 , 6-dimethyl-piperidine-carboxylic acid according to the procedure in Example 14, step (b). Bis-trifluoroacetic acid salt of 5-cyano-1 H-imidazole-2-cyclohex-1-enyl-4- (cis-2,6-dimethyl-piperidin-4-yl) -phenyl] -amide -carboxylic (93 mg, 32%): H NMR (CD3OD; 400 MHz): d 8.17 (d, 1 H, J = 8.4 Hz), 8.03 (s, 1 H), 7.22 (d, 1 H, J = 8.4 Hz), 7.1 1 (s, 1 H), 5.72 ( s broad, 1 H), 3.87 (m, 1 H), 3.78 (m, 1 H), 3.45 (m, 1 H), 3.23 (m, 1 H), 3.07 (m, 1 H), 2.22 (m , 4H), 2.19 (m, 2H), 1.75-1.92 (m, 4H), 1.56 (m, 3H), 1.37 (m, 6H). Mass spectrum, ESI, m / z): calculated for C 24 H 29 N 50, 404.2 (M + H), found 404.2. Bis-trifluoroacetic acid salt of 5-cyano-1 H-imidazole-2-cyclohex-1-enyl-4- (trans-2,6-dimethyl-piperidin-4-yl) -phenyl] -amide -carboxylic (17.3 mg, 56%). 1 H NMR (CDCl 3, 400 MHz): d 13.9 (broad s, 1 H), 10.3 (broad s, 1 H), 9.98 (s, 1 H), 8.41 (d, 1 H, J = 8.4 Hz), 7.75 (s broad, 1 H), 7.26 (dd, 1 H, J = 8.4, 2.0 Hz), 7.15 (d, 1 H, J = 2 Hz), 5.92 (broad s, 1 H), 4.12 (m, 1 H), 3.59 (m, 1 H), 3.1-3.3 (m, 4H), 2.25-2.42 (m, 6H), 2.05-1.78 (m, 6H), 1.62 (d, 3H, J = 7.1 Hz), 1.43 (d, 3H, J = 6.3 Hz). Mass spectrum (ESI, m / z): calculated for C24H29N5O, 404.2 (M + H), found 404.2.

EXAMPLE 52 5-cyano-1H-2-cyclohex-1-enyl-4-ri- (R) - (+) - (2,3-dihydroxy-propionyl) -piperidin-4-phenyl) -amide -imidazole-2-carboxylic acid a) (2-cyclohex-1-enyl-4- [1 - (R) - (+) 2,2-dimethyl-f1, 31-dioxolan-4-carbonyl) -piperidin-4-ill-phenyl) -amide of 5- cyano-1 H-imidazole-2-carboxylic To a solution of methyl (R) - (+) - 2,2-dimethyl-1,3-dioxolan-4-carboxylate (0.16 mL, 1.0 mmol) in MeOH (2 mL) was added 2N KOH ( 0.5 mL, 1 mmol). The resulting solution was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and subjected to sonication for 5 minutes. The ether was then removed and the resulting residue was dried in vacuo for 4 hours to obtain the potassium salt of (R) - (+) - 2,2-dimethyl-1,3-dioxolan-4-carboxylic acid (173). mg, 94%) that was used directly in the next step without purification. To a solution of the trifluoroacetic acid salt of the 4-cyano-1 H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide (as prepared in Example 14, step (b), mg, 0.08 mmol) in DCM (1.5 mL), was added to a mixture of the potassium salt of the acid (R) - (+) - 2,2-dimethyl-1,3-dioxalan-4-carboxylic acid (as prepared above, 18 mg, 0.090 mmol), EDCI (18.8 mg, 0.0900 mmol), HOBt (13.2 mg, 0.0900 mmoles) and DIEA (42 μ? _, 0.24 mmoles). The resulting mixture was stirred at room temperature for 6 hours. Water (10 ml_) was added and the DCM layer was separated, dried (Na 2 SO 4) and concentrated. The residue obtained was chromatographed on silica (2% MeOH / DCM) to obtain the title compound (47 mg, 97%). Mass spectrum (ESI, m / z): calculated for C28H33N5O4, 504.2 (M + H), found 503.9. b) { 2-cyclohex-1-enyl-4- [1- (RW +) - (2,3-dihydroxy-propionyl) -piperidin-4-yl-phenyl) -amide of 5-cyano-1 H-imidazole- 2-carboxylic To a solution of the. { 2-cyclohex-1-enyl-4- [1 - (R) - (2,2-dimethyl- [1, 3] dioxolan-4-carbonyl) -piperidin-4-yl] -phenyl} -amide of 5-cyano-1 H-imidazole-2-carboxylic acid (as prepared in the previous step, 45 mg, 0.090 mmol) in MeOH (1 ml_), 2N aqueous HCl (2 ml_) was added. Mix The resulting mixture was stirred at room temperature for 12 hours. The solvents were removed in vacuo and the resulting residue was dried for 4 hours. Ether (10 ml_) was added and sonicated for 5 minutes. The ether was removed in vacuo and the residue was dried for 12 hours to obtain the title compound (21.3 mg, 52%). H NMR (DMSO, 400 MHz): d 14.1 (broad s, 1H), 9.85 (s, 1H), 8. 32 (s, 1H), 7.92 (d, 1H, J = 8.4 Hz), 7.18 (dd, 1H, J = 8.4, 2.1 Hz), 7.13 (d, 1H, J = 2.1 Hz), 5.72 (s broad, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 4.15 (m, 1H), 3.55 (m, 1H), 3.43 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H) ), 2.63 (m, 1H), 2.12-2.24 (m, 4H), 1.31-1.38 (m, 10 H). Mass spectrum (ESI, miz): calculated for C25H29N504, 464.2 (M + H), found 464.1.

EXAMPLE 53 Salt of trifluoroacetic acid [2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenin-amide of 5-cyano-1H-imidazole-2-carboxylic acid TFA a) 4- (1-Methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl) -phenylamine A solution of N-methoxypiperidinone (J. Org. Chem., 26, 1867, (1961), 650 mg, 5.00 mmol) in THF (20 mL)), cooled to -78 ° C and treated with LDA (1.5 M solution in cyclohex, THF and ethylbenzene, 4.3 mL, 6.4 mmoles) under Ar. The resulting mixture was stirred at the same temperature for 30 minutes and treated with N-phenyltrifluoromethanesulfonimide (2.3 g, 6.4 mmol) in THF (20 mL). The reaction mixture was stirred for another 30 minutes and allowed to warm to room temperature. After 30 minutes at room temperature, the reaction mixture was concentrated in vacuo and the obtained residue was taken up in EtOAc (20 mL) and washed with cold water (2 x 10 mL). The EtOAc layer was dried (Na2SO4) and concentrated to give the 1-methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl ester of trifluoromethanesulfonic acid (980 mg, 71%) as a white foam, which was used directly in the next step. The title compound was then prepared according to the Suzuki coupling procedure of Example 35, step (b), using 4-aminophenylboronic acid (219 mg, 1 .00 mmol) and ester 1-methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl of trifluoromethanesulfonic acid (as prepared above, 261 mg, 1.00 mmol). Chromatography on silica gel (20-50% EtOAc / hexanes) provided 60 mg (29%). Mass spectrum (ESI, m / z): calculated for C12H16N2O, 205.1 (M + H), found 205.2. b) 2-Cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenylamine A solution of 4- (1-methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl) -phenylamine (as prepared in the previous step) (40.8 mg, 0.200 mmol) in MeOH ( 5 mL), was subjected to hydrogenation over 10% Pd / C (20.4 mg) at 1,406 kgf / cm2 (20 psi) for 1 hour. The solution was filtered through a pad of Celite and concentrated to provide 4- (1-methoxy-piperidin-4-yl) -phenylamine (38 mg, 92%), which was used directly in the next step without purification . To a solution of 4- (1-methoxy-piperidin-4-yl) -phenylamine (as prepared above, 42 mg, 0.20 mmol) in DCM (2 mL), NBS (36.2 mg, 0.20 mmol) was added. and the reaction mixture was stirred at temperature environment for 12 hours. The reaction mixture was diluted with DCM (10 ml_) and washed with saturated aqueous NaHCO 3 (10 ml_) and water (10 ml_). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to obtain 2-bromo-4- (1-methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl) -phenylamine (43 mg, 74.5%) that was used in the next step without purification. The title compound was then prepared according to the Suzuki coupling procedure of Example 12, step (d), using cyclohex-1-enyl boronic acid (27.9 mg, 1 .00 mmol) and 2-bromo- 4- (1-methoxy-1, 2,3,6-tetrahydro-pyridin-4-yl) -phenylamine (as prepared above, 44 mg, 0.15 mmol), and chromatographed on silica (20-50). % EtOAc / hexanes), yielding 2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenylamine (33 mg, 74%). Mass spectrum, (ESI, miz): calculated for C18H26N20, 287.2 (M + H), found 286.8. c) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenyl-1-amide -carboxylic A mixture of the potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in Example 3, step (d), 35.6 mg, 0.100 mmol ), DIEA (0.34 μ? _, 0.20 mmol), 2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenylamine (as prepared in the previous step, 28.6 mg, 0.1 mmol) ) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 ml_), was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (10 ml_) and washed with saturated aqueous NaHCO 3 (10 ml_) and water (10 ml_). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The product was chromatographed on silica (20-40% EtOAc / hexane) to obtain the title compound (26 mg, 48%). Mass spectrum (ESI, m / z): calculated for C29H4iN503S, 536.3 (M + H), found 536.2. d) Trifluoroacetic acid salt of 5-cyano-H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenyl-amide] To a solution of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H [2-cyclohex-1-enyl-4- (1-methoxy-piperidin-4-yl) -phenyl] -amide) -imidazol-2- carboxylic acid (as prepared in the previous step, 31 mg, 0.020 mmol) in DCM (0.5 ml_) and EtOH (1 1 μ? _) was added TFA (0.1 ml_). The resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dried for 1 hour, suspended in ether (10 mL) and sonicated for 5 minutes. The solid formed was collected by suction filtration to obtain the title compound (17.3 mg, 58%). 1 H NMR (400 MHz): d 9.70 (s, 1 H), 8.30 (s, 1 H), 7.83 (d, 1 H, J = 8.4 Hz), 7.14 (d, 1 H, J = 8.4 Hz ), 7.05 (s, 1 H), 5.71 (s broad, 1 H), 3.30-3.55 (m, 5H), 2.41 -2.62 (m, 2H), 2.12-2.19 (m, 4H), 1 .60- 1.85 (m, 8H). Mass spectrum (ESI, m / z): calculated for C23H27N5O2, 406.2 (M + H), found 406.1.

EXAMPLE 54 Salt of the trifluoroacetic acid of [6- (4,4-dimethyl-cyclohex-1-enyl) -1 ', 2', 3 ', 4', 5 \ 6'-hexahydro-r2,4'lbipyridinyl- 4-cyano-1 H-imidazole-2-carboxylic acid 5-yl1-amide a) 5-nitrium-3 ', 6'-dihydro-2'H-f2,4'lbipyridinyl-1'-carboxylic acid tert-butyl ester A solution of 202 mg (0.994 mmoles) of 2-bromo-5-nitropyridine in 4 ml_ of toluene and 2 ml of EtOH was treated with 338 mg (1.09 mmoles) of the 4-trifluoromethane-4-trifluoromethane-4-butyl ester. sulfonyloxy-3,6-dihydro-2H-pihdin-1-carboxylic acid (Synthesis, 993, (1991)) and 1.49 mL (2,981 mmol) of 2 M aqueous Na 2 CO 3. The mixture was degassed via sonication, placed under argon, treated with 80.3 mg (0.00700 mmol) of Pd (PPh3) 4 and heated at 80 ° C for 4 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed on a Varigan MegaBond Elut column on 50 g silica with 10-25% EtOAc-hexane, to give 226 mg (75%) of the title compound as a light yellow solid: Mass spectrum ( ESI, m / z): calculated for C15H 9N304, 306.1 (M + H), found 305.7. b) 5-amino-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'-1-bipyridinyl-1'-carboxylic acid tert-butyl ester A solution of 226 mg (0.740 mmol) of the 5-nitro-3 ', 6'-dihydro-2'H- [2,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (as prepared in US Pat. previous step) in 15 mL of MeOH was treated with 10 mg of 10% Pd / C (Degussa type E 01-NE / W, Aldrich, 50% by weight of water) and 1 atmosphere of H2 at room temperature for 18 hours. hours. The mixture was filtered through Celite and the filter cake was washed with MeOH. The concentration gave 220 mg (107%) of the title compound as a colorless glassy solid. Mass spectrum (ESI, m / z): calculated for C15H23N3O2, 278.2 (M + H), found 278.0. c) 5-amino-6-bromo-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'-bipyridinyl-1'-carboxylic acid tert -butyl ester A solution of 220 mg (0.793 mmol) of the 5-amino-3 \ 4 ', 5,, 6'-tetrahydro-2'H- [2,4'] bipyridinyl-1 '- tert-butyl ester carboxyl (as prepared in the previous step) in 10 mL of CH2Cl2 was treated with 134 mg (0.753 mmol) of N-bromosuccinimide at room temperature for 20 minutes. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a Varigan MegaBond Elut column on 50 g silica with 10-35% EtOAc-hexanes gave 209 mg (74%) of the title compound as a colorless glassy solid. H NMR (CDCl 3, 400 MHz): d 6.97 (d, 1 H, J = 8.0 Hz), 6.91 (d, 1 H, J = 8.0 Hz), 4.28-4.15 (broad s, 2H), 4.06-3.90 ( m, 2H), 2.85-2.75 (m, 2H), 2.77-2.68 (m, 1 H), 1.92-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.47 (s, 9H). d) 5-Amino-6- (4,4-dimethy1-cyclohex-1-enyl) -3 ', 4', 5 ', 6'-tetrahydro-2'H- [2-tert -butyl ester] 4'lbipyridinyl-1'-carboxylic acid A solution of 209 mg (0.587 mmol) of the 5-amino-6-bromo-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'] bipyridinyl-tert-butyl ester 1-carboxylic acid (as prepared in the previous step) in 5 mL of toluene and 2.5 mL of EtOH, was treated with 99.3 mg (0.645 mmol) of 4,4-dicyclohex-1-enylboronic acid and 2.34 mL ( 4.69 mmoles) Na 2 C0 3 2 M aqueous. The mixture was degassed via sonication, placed under argon, treated with 47.4 mg (0.0410 mmoles) Pd (PPh3) 4 and heated at 80 ° C for 16 hours. The mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with additional EtOAc and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Chromatography of the residue in a Varigan MegaBond Elut column on 50 g silica with 25% EtOAc-hexanes gave 150 mg (66%) of the title compound as a white foamy solid. Mass spectrum (ESI, m / z): calculated for C23H35N3O2, 386.3 (M + H), found 386.3. e) 5- Tertiary butyl ester. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl-amino) -6- (4,4-dimethyl-cyclohex-1-ene) -3 '. 4'.5'.6'-tetrahydro-2'H-f2.4'1b-pyridinyl-1'-carboxylic acid A solution of 150 mg (0.389 mmol) of the 5-amino-6- (4,4-dimethyl-cyclohex-1-enyl) -3 ', 4', 5 ', 6'-tetrahydro-tert-butyl ester 2'H- [2,4 '] bipyridinyl-1'-carboxylic acid (as prepared in the previous step) in 15 mL of CH2Cl2 was treated with 131 mg (0.428 mmol) of the 4-cyano-1-salt ( Potassium-2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carboxylate (as prepared in Example 3, step (b)), 272 mg (0.584 mmole) PyBroP and 203 μ? _ (1.17 mmole) of DIEA at room temperature for 3 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue in a Varigan MegaBond Elut column on 50 g silica with 50% EtOAc-hexanes gave 215 mg (87%) of the title compound as a white solid. Mass spectrum (ESI, m / z): calculated for C34H5oN604Si, 635.4 (M + H), found 635.3. f) Exit of trifluoroacetic acid from f6- (4,4-dimethyl-cyclohex-1-enyl) -1 \ 2 ', 3', 4 ', 5', 6'-hexahydro-r2,4'1-bipyridinyl-5 4-cyano-1 H-imidazole-2-carboxylic acid-amide A solution of 215 mg (0.339 mmol) of the 5- tert.-butyl ester. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -6- (4Adimethyl-cyclohex-1 -enyl) -3 \ 4 \ 5 \ 6'-tetrahydro-2'H- [2,4 '] bipyridinyl-1'-carboxylic acid (as prepared in the previous step) in 10 mL of CH2Cl2 was treated with three drops of MeOH and 3 mL of TFA at room temperature for 4 hours. MeOH (10 mL) was added, and the solvents were evaporated in vacuo. Chromatography of the residue on a Varigan MegaBond Elut column on 50 g silica with 10% MeOH-CH2Cl2 yielded 210 mg (97%) of the title compound as a white solid. H NMR (CD3OD, 400 MHz): d 8.59 (d, 1 H, J = 8.4 Hz), 8.04 (s, 1 H), 7.28 (d, 1 H, J = 8.4 Hz), 6.02-5.93 (m, 1 H), 3.58-3.48 (m, 2H), 3.32-3.03 (m, 3H), 2.54-2.42 (m, 2H), 2.23-2.02 (m, 6H), 1.1 1 (s, 6H). Mass spectrum (ESI, m / z): calculated for C23H28N6O, 405.2 (M + H), found 405.2.

EXAMPLE 55 Salt of trifluoroacetic acid of f1 '- (2-dimethylamino-acetyl) -6- (4,4-dimethyl-cyclohex-1-nyl) -1 \ 2 \ 3 \ 4 \ 5 \ 6, -hexahydro- 4-cyano-1H-imidazole-2-carboxylic acid f2,4'-1-bipyridinyl-5-yl-1-amide A suspension of 20.9 mg (0.203 mmol) of?,? - dimethylglycine in 4 ml_ of CH2Cl2 was treated with 49.8 mg (0.197 mmol) of bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-CI) and 75 μ? _ (0.54 mmoles) of Et3N at room temperature for 1 hour. The mixture was then treated with 70.0 mg (0.135 mmol) of [6- (4,4-dimethyl-cyclohex-1-enyl) -1 ', 2', 3 ', 4', 5 ', 6 trifluoroacetate. 4-cyano-1 H-imidazole-2-carboxylic acid hexahydro- [2,4 '] bipyridinyl-5-yl] -amide (as prepared in Example 54, step (f)) at room temperature during 18 hours. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA / H2O for 30 minutes to provide 34.9 mg (53%) of the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz): d 8.38 (d, 1 H, J = 8.4 Hz), 8.05 (s, 1 H), 7.33 (d, 1 H, J = 8.4 Hz), 6.05-5.98 (m, 1 H), 4.68 (d, 1 H, J = 15.2 Hz), 3.82 (d, 1 H, J = 15.2 Hz), 3.16-3.05 (m, 1 H), 3.01-2.94 (m, 6H), 2.52 -2.40 (m, 2H), 2.39 (s, 6H), 2.17-2.10 (m, 2H), 2.09-1.87 (m, 2H), 1.67-1.59 (m, 2H), 1. 12 (s, 6H). Mass spectrum (ESI, m / z): calculated for C27H35N7O2, 490.3 (M + H), found 490.4.

EXAMPLE 56 Salt of the trifluoroacetic acid of the r6- (4,4-dimethyl-cyclohex-1-en-1) -1 '- (2-methanesulfonyl-1-yl) -r, 2 \ 3', 4 ', 5' , 4'-cyano-1H-imidazole-2-carboxylic acid 6'-hexahydro-r2,4'-1-bipyridinyl-5-ill-amide A solution of 70.0 mg (0.135 mmol) of [6- (4,4-dimethyl-cyclohex-1-en-1) -1 ', 2', 3 ', 4', 5 ', 6'- 4-cyano-1 H-imidazole-2-carboxylic acid hexahydro- [2,4 '] bipyridinyl-5-yl] -amide (as prepared in Example 54, step (f)) in 10 ml_ of CH2Cl2 was treated with 32.7 mg (0.162 mmol) of the 2-methanesulfonyl-ethyl ester of methanesulfonic acid (as prepared in Example 40, step (a)) and 70.5 pL (0.405 mmoles) of DIEA at room temperature for 6 hours. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by RP-HPLC (C18) with 20-60% CH3CN in 0.1% TFA / H2O for 30 minutes to give 48 mg (85%) of the title compound as a white solid. H NMR (CD3OD, 400 MHz): d 8.65 (d, 1 H, J = 8.4 Hz), 8.05 (s, 1 H), 7.34 (d, 1 H, J = 8.4 Hz), 6.05-5.98 (m, 1 H), 3.85-3.66 (m, 6H), 3.29-3.21 (m, 2H), 3.20-3.01 (m, 1 H), 3.14 (s, 3H), 2.53-2.45 (m, 2H), 2.30- 2.15 (m, 4H), 2.15-2.10 (m, 2H), 1.62 (t, 2H, J = 6.4 Hz), 1.1 1 (s, 6H). Mass spectrum (ESI, m / z): calculated for C26H34N603S, 51 1.2 (M + H), found 51 1 .3.

EXAMPLE 57 Salt of trifluoroacetic acid of. { 5-cyano-1 H-imidazole-2-carboxylic acid 4- [1- (2-amino-2-methyl-propionyl) -piperidin-4-yn-2-cyclohex-1-enyl-phenyl) -amide a) Ter-butyl ester of acid. { 2- [4- (4- { [4-cyano-1 - (2-trimethylsilanyl-ethoxymethyl) -1 H -imdazole-2-carbo-piperidin-1-ill-1,1-dimethyl -2-oxo-ethyl) -carbamic To a solution of 4- (4. {[[4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3- acid. cyclohex-1-enyl-phenyl) -piperidine-1-carboxylic acid (231 mg, 0.380 mmol) (as prepared in Example 14, step (a)) in 2.5 mL of DCM and 0.4 mL of EtOH, was added 700 pL of TFA and the solution was stirred for 3 hours at 25 ° C. The reaction was diluted with 4 mL of EtOH and then concentrated to provide approximately a 2: 1 mixture of the trifluoroacetic acid salt of the (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl) -amide. 5-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid to the raw material by 1 H NMR and LC / MS, which was used in the next step without further purification. The mixture in 3 mL of DCM was added to a solution of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (53 mg, 0.70 mmol), DIEA (122 pL, 0.700 mmol) and PyBroP (144 mg, 0.300 mmol) in 3 mL of DCM, and the The reaction was stirred at 25 ° C overnight. The reaction was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (1 x 25 mL) and brine (25 mL), and the organic layer was dried over Na2SO4 and then concentrated. Purification of the residue by preparative TLC (50% EtOAc-hexanes) gave 40 mg (15%) of the title compound as a white solid. Mass spectrum (ESI, m / z): calculated for C37H55N6O5YES, 691.3 (M + H), found 691.1. b) Trifluoroacetic acid salt of 5-cyano- (4- [1- (2-amino-2-methyl-propionyl) -piperidin-4-yn-2-cyclohex-1-enyl-phenyl) -amide 1 H-imidazole-2-carboxylic acid To a solution of the ter-butyl ester of the acid. { 2- [4- (4- { [4-cyano-1 - (2-trimethylsilanyl-ethoxymethyl) -1 H -imidazole-2-carbonyl] -amino.} - 3-cyclohex-1-enyl-phenyl ) -piperidin-1-yl] -1, 1-dimethyl-2-oxo-ethyl} -carbamic (40 mg, 0.050 mmol) in 2 mL of DCM and 20 pL of EtOH were added 1.5 mL of TFA. The solution was stirred for 3 hours at 25 ° C, diluted with 2 mL of EtOH and concentrated in vacuo. Trituration of the residue with ether afforded 8.4 mg (29%) of the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz): d 8.10 (d, 1 H, J = 8.4 Hz), 8.00 (s, 1 H), 7.16 (d, 1 H, J = 8.4 Hz), 7.07 (s, 1 H ), 5.79 (s, 1 H), 4.55-4.48 (m, 1 H), 3.30 (s, 6H), 2.89-2.87 (m, 2H), 2.40-2.25 (m, 4H), 1 .96-1.93 (m, 2H), 1.86-1.83 (m, 6H), 1.64-1.61 (m, 2H). Mass spectrum (ESI, m / z): calculated for C 26 H 33 N 6 O 2, 461.2 (M + H), found 461.3.

EXAMPLE 58 r6-cyclohex-1-enyl-1 '- (2-methanesulfonyl-ethyl) -1', 2 ', 3', 4 ', 5', 6'-hexahydro- and 2,4'1-bipyridinyl-5-in 5-cyano-1H-imidazole-2-carboxylic acid amide a) 5-amino-6-cyclohex-1-enyl-3 ', 4', 5l, 6'-tetrahydro-2'H-f2,4'lbipyridinyl-1'-carboxylic acid tert-butyl ester A mixture of the 5-amino-6-bromo-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'] bipyridinyl-r-carboxylic acid tert -butyl ester (331 mg, 0.93 mmole) (as prepared in Example 54, step (c)) and cyclohexen-1-yl boronic acid (141 mg, 1.1 1 mmoles) in 5 ml_ of EtOH, 10 ml of toluene and 5 ml_ of 2 M Na2CO3. , was added to Pd (PPh3) 4 (107 mg, 0.0930 mmol), and the resulting mixture was heated at 80 ° C for 16 hours. The reaction was diluted with 100 mL of ether and 100 mL of brine and the layers separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, 30-60% ether-hexanes), afforded 248 mg (74%) of the title compound as a light brown oil. LC-MS (ESI, m / z): calculated for C 21 H 32 N 302 (M + H), 358.2, found 358.1. b) 5- Tert-butyl ester. { [4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonin-amino) -6-cyclohex-1-enyl-3 ', 4', 5 ', 6'-tetrahydro-2 'H-f2,4'lbipyridinyl-1' -carboxylic acid To a solution of the salt of potassium 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-2-carboxylate (296 mg, 0.970 mmol) (as prepared in Example 3, step (d) )) in 8 mL of DCM, DIEA (291 pL, 1.72 mmol) and PyBroP (512 mg, 1.10 mmol) were added and the reaction was stirred at 25 ° C for 15 minutes. A solution of the 5-amino-6-cyclohex-1-ene-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'] bipyridinyl-1-tert-butyl ester Carboxylic acid (233 mg, 0.65 mmol) (as prepared in the previous step) in 4 mL of DCM was added, and the reaction was stirred overnight at 25 ° C. The reaction was diluted with EtOAc (25 mL) and washed with NaHCO 3 (1 x 25 mL) and brine (25 mL), and the organic layer was dried over Na 2 SO and then concentrated. The residue was purified by flash chromatography (silica gel, 5% MeOH-CHCl3), to give 167 mg (40%) of the title compound as a white solid. Mass spectrum (ESI, m / z): calculated for C32H46N604Si, 607.3 (M + H), found 607.3. c) Exit of trifluoroacetic acid from (6-cyclohex-1-enyl-1 ', 2'.3'.4'.5'.6'-hexahydro- [2,4'-bipyridinyl-5-yl) -amide of 5-cyano-1 H-imidazole-2-carboxylic acid The title compound was prepared from the 5- tert.-butyl ester. { [4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -6-cyclohex-1-enyl-3 \ 4,, 5,, 6'-tetrahydro-2'H- [2,4 '] bipyridinyl-1'-carboxylic acid (167 mg, 0.27 mmol) using a procedure similar to Example 14, step (b) to provide 57 mg (43%) of the title compound as a white solid. LC-MS (ESI, m / z): calculated for C2iH24N60, 377.2 (M + H), found 377.2. d) [6-cyclohex-1-enyl-r- (2-methanesulfonyl-et) l) -1 ', 2', 3 ', 4,, 5'.6'-hexahydro- [2,4'-bipyridi 5-cyano-1 H-imidazole-2-carboxylic acid nyl-5-n-amide A suspension of the trifluoroacetic acid salt of (6-cyclohex-1-enyl-1 \ 2 \ 3 \ 4 \ 5'-hexahydro- [2,4-bipyridinyl-5-yl) -amide of 5-cyano-1 H-imidazole-2-carboxylic acid (57 mg, 0.1 1 mmol) in 5 mL of DCM was added DIEA ( 50.4 pL, 0.290 mmol) followed by 30.5 mg (0.150 mmol) of the 2-methanesulfonyl-ethyl methanesulfonic acid ester (as prepared in Example 40, step (a)). The reaction was allowed to stir overnight, was diluted with 20 mL of DCM, washed with saturated aqueous NaHCO3 (1 x 20 mL) and dried over Na2SO4. Purification by preparative TLC (silica gel, 40% EtOAc-hexanes), gave 22.3 mg (40%) of the title compound as a white solid. H NMR (DMSO, 400 MHz): d 10.02 (s, 1 H), 8.24 (s, 1 H), 8.1 1 (d, 1 H, J = 8.4 Hz), 7.18 (d, 1 H, J = 8.4 Hz), 5.96 (s, 1 H), 3.04 (s, 3H), 3.02-2.99 (m, 3H), 2.73 (t, 2H, J = 2.7 Hz), 2.39-2.37 (m, 2H), 2.1 1 -2.05 (m, 4H), 1 .85-1.64 (m, 10H). Mass spectrum (ESI, m / z): calculated for C 24 H 31 N 6 O 3 S, 483.2 (M + H), found 483.3.

EXAMPLE 59 An alternative method for the synthesis of the intermediate described in Example 3 is described below.

Potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) - H-imidazole-2-carboxylic acid a) 1 H-lmidazole-4-carbonitrile A round-bottomed, four-necked, 22 L flask equipped with a mechanical stirrer, a temperature probe, a condenser and an addition funnel with a nitrogen inlet was charged with 1 H-imidazole-4-carboxaldehyde (Aldrich , 1.10 kg, 1.5 mol) and pyridine (3.0 L, 3.0 mol). The reaction flask was cooled to 8 ° C with an ice bath and hydroxylamine hydrochloride (871 g) was added slowly., 12.5 moles) in portions to keep the internal temperature below 30 ° C. The reaction was allowed to cool to room temperature and was stirred for 2 hours at room temperature. The resulting thick yellow solution was heated at 80 ° C with a heating mantle and acetic anhydride (2.04 L, 21.6 moles) was added dropwise over 200 minutes to maintain the temperature below 1 10 ° C during the addition. The reaction mixture it was heated at 100 ° C for 30 minutes, time after which it was allowed to cool to room temperature and then further cooled in an ice bath. The pH was adjusted to 8.0 (pH meter) by the addition of 25% by weight of NaOH (5.5 L) at a ratio such that the internal temperature remained below 30 ° C. The reaction mixture was then transferred into a 22 L separatory funnel and extracted with ethyl acetate (6.0 L). The combined organic layer was washed with brine (2 x 4.0 L), dried over MgSO 4, filtered and concentrated to dryness under reduced pressure at 35 ° C to give the crude product as a yellow semi-solid. The resulting yellow semi-solid was suspended in toluene (3.0 L) and stirred for 1 hour, after which time it was filtered to give a light yellow solid, which was resuspended in toluene (3.0 L) and stirred for 1 hour. The resulting suspension was filtered and the filter cake was washed with toluene (2 x 500 mL) to give the title compound as a light yellow solid [870 g, 82%). The spectrum of 1H and 13C NMR were consistent with the assigned structure. b) 1- (2-trimethylsilyl-ethoxymethyl) -1 H-imidazole-4-carbonitrile and 3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazole-4-carbonitrile A 22-L, four-necked, round-bottomed flask equipped with a mechanical stirrer, a temperature probe and an addition funnel with a nitrogen inlet was charged with 1 H-imidazole-4-carbonitrile (830 g, 8.91 g. moles, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 moles) and acetone (6.0 L). Stirring was started and the mixture was cooled to 10 ° C with an ice bath. SEMCI (1.50 kg, 9.00 moles) was added through the addition funnel for 210 minutes to maintain the internal temperature below 15 ° C. The reaction was then allowed to warm to room temperature and stirred at room temperature overnight (20 hours). The reaction mixture was then cooled in an ice bath at 10 ° C and quenched by the slow addition of water (8.0 L) for 30 minutes to keep the internal temperature below 30 ° C. The resulting mixture was transferred to a 22 L separatory funnel and extracted with ethyl acetate (2 x 7.0 L). The combined organics were concentrated under reduced pressure at 35 ° C to provide the crude product as a dark brown oil, which was purified through of a plug of silica gel (16.5 x 20 cm, 2.4 kg of silica gel) using 2: 1 heptane / ethyl acetate (15 L) as eluent. Fractions containing the product were combined and concentrated under reduced pressure at 35 ° C to provide a mixture of the title compounds as a light brown oil [1785 g, 90%). The 1 H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of the regioisomers. c) 2-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1 H-imidazole-4-carbonitrile A 22 L, four-necked, round bottom flask equipped with a mechanical stirrer, a temperature probe and a condenser with a nitrogen inlet was charged with a mixture of 1- (2-tnmethylsilanyl-ethoxymethyl) -1 H -imidazole-4-carbonitrile and 3- (2-trimethylsilanyl-ethoxymethyl) -3H-imidazole-4-carbonitrile [600 g, 2.69 moles, as prepared in the previous step) and carbon tetrachloride (1.8 L). The stirring was started and the mixture was heated to 60 ° C. At this point, N-bromosuccinimide (502 g, 2.82 moles) was added in several portions for 30 minutes, which resulted in an exotherm at 74 ° C. The reaction was allowed to cool to 60 ° C and was further stirred at 60 ° C. C for 1 hour. The reaction was allowed to cool slowly at room temperature and the resulting suspension was filtered and the filtrate was washed with a solution of aqueous NaHCO3 (4.0 L). The organics were passed through a plug of silica gel (8 x 15 cm, silica gel, 600 g) using 2: 1 heptane / ethyl acetate (6.0 L) as eluent. The fractions containing the product (based on a TLC analysis) were combined and concentrated under reduced pressure to give a light yellow crystalline solid, which was then filtered and washed with heptane (500 mL) to provide the title compound. title as a crystalline white solid [593 g, 73%). The spectrum of 1H and 13C NMR was consistent with the assigned structure and showed no evidence of the minor regioisomer. d) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester SEM A 12 L, four-necked, round bottom flask equipped with a mechanical stirrer, a temperature probe and an addition funnel with a nitrogen inlet was charged with 2-bromo-1- (2-trimethylsilyl-ethoxymethyl) -1 H-imidazole-4-carbonitrile [390 g, 1.29 moles, as prepared in the previous step) and anhydrous tetrahydrofuran (4.0 L). Agitation was started and the reaction mixture was cooled to -50 ° C using an ice bath dry / acetone. Isopropylmagnesium chloride (2.0 M in THF, 760 ml, 1.52 moles) was added through the addition funnel for 30 minutes to maintain the internal temperature below -40 ° C. The reaction was stirred for an additional 30 minutes at -43 ° C, after which time it was cooled to -78 ° C. Ethyl chloroformate (210 ml_, 2.20 moles) was added through the addition funnel for 10 minutes to keep the internal temperature below -60 ° C. The reaction was stirred for an additional 40 minutes at -70 ° C, at which point the dry ice / acetone bath was removed, and the reaction was allowed to warm to room temperature for 1.5 hours. The reaction mixture was cooled in an ice bath at 0 ° C and quenched by the slow addition of a saturated solution of ammonium chloride (1.8 L) at a ratio such that the internal temperature was kept below 10 ° C. ° C. The reaction mixture was transferred into a 12 L separatory funnel, diluted with ethyl acetate (4.0 L) and the layers separated. The organic layer was washed with brine (2 x 2.0 L) and concentrated under reduced pressure at 35 ° C to provide a brown oil. The crude oil was dissolved in dichloromethane (300 mL) and purified by chromatography (15 x 22 cm, 1.5 kg of silica gel, 10: 1 to 4: 1 heptane / ethyl acetate) to give a yellow oil, which was dissolved in EtOAc (100 mL), diluted with heptane (2.0 L) and stored in a refrigerator for 5 hours. The resulting suspension was filtered to give the title compound as a white crystalline solid (141 g, 37%). The spectrum of H and 13C NMR was consistent with the assigned structure. e) Potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid A 5-L, three-necked, round bottom flask equipped with a mechanical stirrer, a temperature probe and an addition funnel with a nitrogen inlet was charged with 5 [400 g, 1.35 mol) and ethanol (4.0 L) ). Agitation was started and a water bath was applied after all the solid had dissolved. A solution of 6 N KOH (214.0 ml_, 1.29 moles) was added through the addition funnel for 15 minutes to keep the internal temperature below 25 ° C and the reaction was stirred for 5 minutes at room temperature. The solution was then concentrated to dryness under reduced pressure at 20 ° C to provide a white solid. The resulting solid was suspended in methyl t-butyl ether (MTBE, 4.0 L) and stirred for 30 minutes, after which time the suspension was filtered and the filter cake was washed with MTBE (1.0 L), provide the title compound as a white solid, which was further dried under vacuum at room temperature for 4 days [366 g, 89%). The 1 H NMR, 3 C NMR and the mass spectrum were consistent with the assigned structure. Analysis calculated for C11 H16KN3O3YES: C, 43.25; H, 5.28; N, 13.76. Found: C, 42.77; H, 5.15; N, 13.37. Karl Fisher: 1.3% H20.

BIOLOGICAL ACTIVITY IN VITRO ASSAYS The following representative in vitro assays were performed to determine the biological activity of C-KIT of the compounds of Formula I. They are provided to illustrate the invention in a non-limiting manner.

Fluorescence polarization kinase assay of c-kit The compounds of the present invention are also specific inhibitors of c-Kit. The Selection of the preferred compounds of Formula I for use as inhibitors of c-Kit were performed in the following manner using an in vitro kinase assay to measure the inhibition of the kinase domain isolated from the human c-kit receptor in a protocol polarization with fluorescence (FP). The c-kit assay used the fluorescein-labeled phosphopeptide and the antiphosphorin antibody included in the Fosfo-Tyrosine Kinase Panvera (Green) Kit supplied by Invitrogen. When c-kit phosphorylated the poly Glu4Tyr, the fluorescein-labeled phosphopeptide was displaced from the antiphosphotyrosine antibody by the phosphorylated poly Glu 4 Tyr, thus decreasing the FP value. The kinase reaction of the c-kit was incubated at room temperature for 45 minutes under the following conditions: 1 nM c-kit (ProQinase, lot SP005), 100 μg / ml poly Glu 4 Tyr, 50 uM ATP, 5 mM MgCl 2, 1 mM DTT, 0.01% Tween-20, 1% DMSO or 100 nM Hepes compound, pH 7.5. The reaction of the kinase was stopped by the addition of EDTA. The fluorescein-labeled phosphopeptide and the Antiphosphotyrosine antibody was added and incubated for 30 minutes at room temperature and polarization was read with fluorescence. The data points were an average of samples in triplicate. Analysis of the inhibition and Cl50 data were done with GraphPad Prism using a non-linear regression fit with a dose response equation (variable slope) sigmoidal, with multiple parameters. The IC50 for inhibition of the kinase represents the dose of a compound that results in a 50% inhibition of kinase activity as compared to the vehicle control of DMSO.

BR-1 Assay of the c-Kit BR-1 cells are a dog mastocytoma line expressing a constitutive active mutant KIT (Ma Y., BJ Longley, X. Wang, JL Blount, K. Langley, GH Caughey. Clustering of activating mutations in c-kit's juxtamembrane coding region in canine mast cell neoplasms J Invest Dermatol 1 12: 165-170, 1999.). The proliferation of BR-1 cells can be inhibited by KIT inhibitors and there is a good relationship between the potency of the compound in the KIT enzyme assays and the inhibition of BR-1 proliferation. To test the inhibition of BR-1 cell proliferation, BR-1 cells are suspended (1 million cells / ml) in DMEM (Eagle's Medium Modified by Delbeccio) containing 10% FCS and 100 μ? / ???? they are plated in 96-well culture plates with a transparent bottom (CoStar 3610) containing 50 μ? from the same medium supplemented with serial dilutions of the test compounds. Immediately after plating (time zero), 6 wells containing the cells were treated with 100 μ? of the Cell TiterGIo Promega reagent and incubated for 10 minutes with shaking. The intensity of the Cell TiterGIo signal (1 second / well) was determined using a luminometer. The remaining cells were cultured 72 hours (37 ° C and 5% CO2). After the 72 hour growth interval, 100 μ? of Cell TiterGIo Reagent Promega to each well. The plates were incubated an additional 10 minutes with shaking and the intensity of the Cell TiterGIo signal (1 second / well) was determined using a luminometer. Cell proliferation is defined by the difference between the zero-time and 72-hour signals. The Cl 50 values of the test compounds were calculated as the concentrations resulting in 50% inhibition of growth.

Biological data Biological data for C-KIT The activity of the selected compounds of the present invention is presented below. All activities are in μ? and have the following uncertainties: C-KIT kinase: + 10%.

Methods of treatment / prevention The present invention comprises the use of the compounds of the present invention to inhibit the activity of the C-KIT kinase in a cell or a subject, or to treat disorders related to the activity or expression of the kinase. of the C-KIT in a subject. In one embodiment of this aspect, the present invention provides a method for reducing or inhibiting the activity of the C-KIT kinase in a cell, comprising the step of contacting the cell with a compound of the present invention. The present invention also provides a method for reducing or inhibiting the kinase activity of C-KIT in a subject, comprising the step of administering a compound of the present invention to the subject. The present invention further provides a method for inhibiting cell proliferation in a cell, comprising the step of contacting the cell with a compound of the present invention. The activity of the C-KIT kinase in a cell or a subject can be determined by methods well known in the art, such as the C-KIT kinase assay described herein. The term "subject" as used herein, refers to an animal, preferably a mammal, more preferably a human, which has been the subject of treatment, observation or experiment.

The term "contacting" as used herein, refers to the addition of the compound to cells, so that the compound is taken up by the cell. In other embodiments of this aspect, the present invention provides prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to C-KIT. In one example, the invention provides methods for preventing in a subject a cell proliferative disorder or a disorder related to C-KIT, which comprises administering to the subject a prophylactically effective amount of a pharmaceutical composition comprising a compound of the present invention and a carrier. pharmaceutically acceptable. The administration of the prophylactic agent can occur before the manifestation of the characteristic symptoms of the cell proliferative disorder or the C-KIT related disorder, so that a disease or disorder is avoided, or alternatively, its progression is delayed. In another example, the invention pertains to methods for treating in a subject a cell proliferative disorder or a disorder related to C-KIT, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The administration of the therapeutic agent may occur concurrently with the manifestation of the characteristic symptoms of the disorder, so that the therapeutic agent serves as a therapy to compensate for the cell proliferative disorder or disorders related to C-KIT. The term "prophylactically effective amount" refers to an amount of an active compound or pharmaceutical agent that inhibits or delays in a subject the onset of a disorder, which is sought by a researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" as used herein, refers to an amount of the active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject, which is sought by a researcher, veterinarian, medical doctor or other clinical, which includes relief of the symptoms of the disease or disorder being treated. Methods for determining therapeutically and prophylactically effective doses for pharmaceutical compositions comprising a compound of the present invention are described herein and are known in the art. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combinations of the specified ingredients in the specified amounts. . As used herein, the terms "disorders related to C-KIT", or "disorders related to the C-KIT receptor", or "C-KIT receptor tyrosine kinase related disorders" will include diseases associated with or involving the activity of C-KIT, for example, the overactivity of C-KIT and conditions that accompany these diseases. The term "C-KIT overactivity" refers to 1) the expression of C-KIT in cells that do not normally express C-KIT; 2) the expression of C-KIT by cells that do not normally express C-KIT; 3) increased C-KIT expression leading to undesired cell proliferation or 4) mutations leading to constitutive activation of C-KIT. Examples of "C-KIT-related disorders" include disorders that result from over-stimulation of C-KIT due to an abnormally high amount of C-KIT or mutations in C-KIT, or disorders resulting from an abnormally high amount of C-KIT. C-KIT activity due to an abnormally high amount of C-KIT or mutations in C-KIT. It is known that the overactivity of C-KIT has been implicated in the pathogenesis of several diseases, including the cell proliferative disorders, neoplastic disorders and cancers listed below. The term "cell proliferative disorders" refers to the unwanted cell proliferation of one or more subsets of cells in a multicellular organism that results in damage (i.e., discomfort or decreased life expectancy) to multicellular organisms. Cell proliferative disorders can occur in different types of animals and humans. As used herein "cell proliferative disorders" include neoplastic disorders.

As used herein, a "neoplastic disorder" refers to a tumor that results from abnormal or uncontrolled cell growth. Examples of neoplastic disorders include, but are not limited to, hematopoietic disorders such as, for example, myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM). , chronic idiopathic myelofibrosis (MFI) and polycythemia vera (PV), cytopenias and premalignant myelodysplastic syndromes; cancers such as glioma cancers, lung cancers, breast cancers, colorectal cancers, prostate cancers, gastric cancers, gastrointestinal stromal tumors (GIST), esophageal cancers, colon cancers, pancreatic cancers, ovarian cancers and hematologic malignancies, including myelodysplasia, multiple myeloma, leukemias and lymphomas. Examples of hematologic malignancies include, for example, leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma) and myeloma, for example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML) ), juvenile myelomonocytic leukemia (JMML), ALL of T lymphocytes in adults, AML with myelodysplasia of three lineages (AML TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD) and multiple myeloma (MM). In a further embodiment of this aspect, the invention encompasses a combination therapy for treating or inhibiting the onset of a cell proliferative disorder or a disorder related to C-KIT in a subject. The combination therapy comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of the present invention and one or more other cell anti-proliferation therapies, including chemotherapy, radiation therapy, gene therapy and immunotherapy. In one embodiment of the present invention, a compound of the present invention can be administered in combination with chemotherapy. As used herein, chemotherapy refers to a therapy that involves a chemotherapeutic agent. A variety of chemotherapeutic agents can be used in the combined treatment methods described herein. Exemplary chemotherapeutic agents, include, but are not limited to: platinum compounds (eg, cisplatin, carboplatin, oxaliplatin); taxane compounds (e.g., paclitaxcel, docetaxol); campotothecin compounds (irinotecan, topotecan); vincaalkaloids (for example, vincristine, vinblastine, vinorrelbine); antitumor nucleoside derivatives (e.g., 5-fluorouracil, leucovorin, gemcitabine, capecitabine), alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, thiotepa); epipodophyllotoxins / podophyllotoxins (e.g., etoposide, teniposide); inhibitors of aromatase (for example, anastrozole, letrozole, exemestane); antiestrogenic compounds (e.g., tamoxifen, fulvestrant), antifolates (e.g., premetrexed disodium); hypomethylating agents (e.g., azacitidine); biological compounds (for example, gemtuzamab, cetuximab, rituximab, pertuzumab, trastuzumab, bevacizumab, erlotinib); antibiotics / anthracyclines (for example idarubicin, actinomycin D, bleomycin, daunorubicin, doxorubicin, mitomycin C, dactinomycin, carminomycin, daunomycin); antimetabolites (for example, aminopterin, clofarabine, cytosine arabinoside, methotrexate); agents that bind to tubulin (for example combretastatin, colchicine, nocodazole); topoisomerase inhibitors (eg, camptothecin). Additional useful agents include verapamil, a calcium antagonist that was found to be useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potential the efficacy of such compounds in drug-sensitive malignancies. . See, Simpson WG, The calcium channel blocker verapamil and cancer chemotherapy. Cell Calcium. 1985 Dec; 6 (6): 449-67. In addition, chemotherapeutic agents yet to emerge are contemplated as useful in combination with a compound of the present invention. In another embodiment of the present invention, the compounds of the present invention can be administered in combination with radiation therapy. As used herein, "radiation therapy" refers to a therapy that comprises exposing the subject in need thereof to radiation. Such therapy is known to those skilled in the art. The appropriate scheme of radiation therapy will be similar to those already employed in clinical therapies where radiation therapy is used alone or in combination with other chemotherapeutic agents. In another embodiment of the present invention, the compounds of the present invention can be administered in combination with gene therapy. As used in the present "therapy quenica" refers to a therapy that is directed to particular genes involved in the development of the tumor. Possible gene therapy strategies include the restoration of defective cancer inhibitory genes, transduction or transfection of cells with antisense DNA corresponding to the genes encoding growth factors and their receptors, RNA-based strategies such as ribozymes, RNA lures, antisense messenger RNAs and small interfering RNA molecules (siRNA) and so-called "suicide genes". In other embodiments of this invention, the compounds of the present invention may be administered in combination with immunotherapy. As used herein, "immunotherapy" refers to a therapy directed to a particular protein involved in the development of the tumor, via antibodies specific for such a protein. For example, monoclonal antibodies against vascular endothelial growth factor have been used to treat cancers.

Where a second pharmaceutical product is used in addition to a compound of the present invention, the two pharmaceutical products can be administered simultaneously (eg, in separate or unit compositions), sequentially in any order, at about the same time or in schedules of separate dosing. In the latter case, the two compounds will be administered in a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the method and order of administration and the respective dosage amounts and preferred regimens for each component of the combination will depend on the particular chemotherapeutic agent being administered, in conjunction with the compound of the present invention, its route of administration. administration, the particular tumor being treated and the particular host being treated. As will be understood by those of ordinary skill in the art, appropriate doses of the chemotherapeutic agents will generally be similar to, or less than, those already employed in clinical therapies, wherein the chemotherapeutic agents are administered alone or in combination with other chemotherapeutic agents. . The method and order of administration and the amounts of the optimal dosage and regime can be readily determined by those skilled in the art, using conventional methods and in view of the information set forth herein.

By way of example only, the platinum compounds are advantageously administered in a dosage of 1 to 500 mg per square meter (mg / m2) of body surface area, for example 50 to 400 mg / m2, particularly for cisplatin in a dosage of approximately 75 mg / m2 and for carboplatin in approximately 300 mg / m2 per course of treatment. Cisplatin is not orally absorbed and therefore, it must be administered via injection intravenously, subcutaneously, intratumorally or intraperitoneally. By way of example only, the taxane compounds are advantageously administered in a dosage of 50 to 400 mg per square meter (mg / m2) of body surface area, eg, 75 to 250 mg / m2, particularly for the paclitaxel in a dosage of approximately 175 to 250 mg / m2 and for docetaxel in approximately 75 to 150 mg / m2 per course of treatment. By way of example only, camptothecin compounds are advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg / m2) of body surface area, for example, 1 to 300 mg / m2, particularly for the irinotecan in a dosage of approximately 100 to 350 mg / m2 and for the topotecan in approximately 1 to 2 mg / m2 per course of treatment. By way of example only, vincaalkaloids can be advantageously administered in a dosage of 2 to 30 mg per square meter (mg / m2) of body surface area, particularly for vinblastine in a dosage of approximately 3 to 12 mg / m2, for vincristine in a dosage of approximately 1 to 2 mg / m2 and for vinorrelbine in a dosage of approximately 10 to 30 mg / m2 per course of treatment. By way of example only, the antitumor nucleoside derivatives can be advantageously administered in a dosage of 200 to 2500 mg per square meter (mg / m2) of body surface area, for example, 700 to 1500 mg / m2. 5-Fluorouracil (5-FU) is commonly used via intravenous administration with doses ranging from 200 to 500 mg / m2 (preferably from 3 to 15 mg / kg / day). Gemcitabine is advantageously administered in a dosage of approximately 800 to 1200 mg / m2 and capecitabine is advantageously administered in approximately 1000 to 2500 mg / m2 per course of treatment. By way of example only, the alkylating agents can be advantageously administered in a dosage of 100 to 500 mg per square meter (mg / m2) of body surface area, for example, 120 to 200 mg / m2, particularly for cyclophosphamide in a dosage of approximately 100 to 500 mg / m2, for chlorambucil in a dosage of approximately 0.1 to 0.2 mg / kg of body weight, for carmustine in a dosage of approximately 150 to 200 mg / m2 and for lomustine in a dosage of approximately 100 to 150 mg / m2 per course of treatment.

By way of example only, the podophyllotoxin derivatives can be advantageously administered in a dosage of 30 to 300 mg per square meter (mg / m2) of body surface area, for example, 50 to 250 mg / m2, particularly for the etoposide in a dosage of approximately 35 to 100 mg / m2 and for the teniposide in approximately 50 to 250 mg / m2 per course of treatment. By way of example only, the anthracycline derivatives can be advantageously administered in a dosage of 10 to 75 mg per square meter (mg / m2) of body surface area, for example 15 to 60 mg / m2, particularly for the doxorubicin in a dosage of approximately 40 to 75 mg / m2, for daunorubicin in a dosage of approximately 25 to 45 mg / m2 and for idarubicin in a dosage of approximately 10 to 15 mg / m2 per course of treatment. By way of example only, the antiestrogen compounds can be advantageously administered in a dosage of about 1 to 100 mg daily, depending on the particular agent and the condition being treated. Tamoxifen is administered orally advantageously in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for a sufficient time to achieve and maintain a therapeutic effect. Toremifene is administered orally advantageously in a dosage of approximately 60 mg once a day, continuing therapy for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is given orally advantageously in a dosage of about 1 mg once a day. Droloxifene is administered orally advantageously in a dosage of approximately 20-1 OOmg once a day. Raloxifene is administered orally advantageously in a dosage of approximately 60 mg once a day. Exemestane is administered orally advantageously in a dosage of approximately 25 mg once a day. By way of example only, the biological compounds can be advantageously administered in a dosage of about 1 to 5 mg per square meter (mg / m2) of body surface area, or as is known in the art, if different. For example, trastuzumab is advantageously administered in a dosage of 1 to 5 mg / m2 particularly 2 to 4 mg / m2 per course of treatment. The dosages may be administered, for example, once, twice or more per course of treatment, which can be repeated for example, every 7, 14, 21 or 28 days. The compounds of the present invention can be administered to a subject systemically, for example, intravenously, orally, subcutaneously, intramuscularly, intradermally or parenterally. The compounds of the present invention can also be administered to a subject locally. Non-limiting examples of local delivery systems include the use of intraluminal medical devices that include catheters for the intravascular delivery of drugs, wires, pharmacological stents and endoluminal coatings. A compound of the present invention can be further administered to a subject in combination with a targeting agent to achieve a high target concentration of the compound at the target site. In addition, the compounds of the present invention can be formulated for rapid release or slow release in order to keep the drugs or agents in contact with the target tissues for a period ranging from hours to weeks. The present invention also provides a pharmaceutical composition comprising a compound of the present invention, in association with a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 100 to 500 mg, of the compound and may be constituted in any suitable form for the selected mode of administration. The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse reaction, allergic or other undesired reaction when administered to an animal, or a human, as appropriate. Veterinary uses are also included within the invention and "pharmaceutically acceptable" formulations include formulations for clinical and / or veterinary use. The carriers include the necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavors, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release formulations, synchronized release and sustained release), granules and powders and liquid forms, such as solutions, syrups , elixirs, emulsions and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions and suspensions. The pharmaceutical compositions of the present invention also include a pharmaceutical composition for the slow release of the compounds of the present invention. The composition includes a slow release carrier (typically, a polymeric carrier) and a compound of the present invention. Slow-release biodegradable carriers are well known in the art. These are materials that can form particles that capture an active compound therein and slowly degrade / dissolve under a suitable medium (eg, aqueous, acidic, basic, etc.), and therefore degrade / dissolve in fluids body and release the active compound in them. The particles are preferably nanoparticles (ie in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter and more preferably about 100 nm in diameter). The present invention also provides methods for preparing the pharmaceutical compositions of the invention. A compound of The present invention, as the active ingredient, is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical composition techniques, carrier which can take a wide variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral, such as intramuscular. In the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, such as, for example, powders, capsules, oblong tablets, gel capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case, solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated with sugar or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, although other ingredients, for example, for purposes of assisting in solubility or for preservation, may be included. Injectable suspensions can also be prepared, in which case carriers, liquid suspending agents can be used appropriate and similar. In a preparation for slow release, a slow release carrier, typically a polymeric carrier and a compound of the present invention, is dissolved or dispersed first in an organic solvent. The organic solution obtained is then added to an aqueous solution to obtain an emulsion of the oil-in-water type. Preferably, the aqueous solution includes surfactants. Subsequently, the organic solvent is evaporated from the oil-in-water emulsion to obtain a colloidal suspension of particles containing the slow-release carrier and the compound of the present invention. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per dosage unit, for example, tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.01 mg to 200 mg / kg of body weight per day. Preferably, the range is from about 0.03 to about 100 mg / kg of body weight per day, more preferably, from about 0.05 to about 10 mg / kg of body weight per day. The compound can be administered in a regime of 1 to 5 times per day. The dosages, however, may vary depending on the requirement of the patients, the severity of the condition being treated and the compounds being employed. The use of daily administration or post-periodic dosing may be employed. Preferably, these compositions are a unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parental solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, the composition may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a reservoir preparation for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed uniformly throughout the composition, so that the composition can be easily subdivided into dosage forms equally effective such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above, containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the composition of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of a prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a wrap over the first. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum or to delay its release. A variety of materials can be used for such enteric coatings or coatings, such materials include various polymeric acids with materials such as lacquer, acetyl alcohol and cellulose acetate. Liquid forms in which a compound of the present invention can be incorporated for oral administration or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, oil of sesame, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic gums and natural such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Liquid forms in suitably flavored suspension or dispersing agents can also include synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like. For parenteral administration, suspensions and sterile solutions are desired. Isotonic preparations containing generally suitable preservatives are used when intravenous administration is desired. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses, two, three or four times a day. In addition, the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles or via transdermal skin patches, well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the administration of the dosage will be, by compound, continuous rather than intermittent through the dosing regimen. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as ethanol, glycerol, water and the like. In addition, when desired or necessary, binders, lubricants, disintegrating agents and suitable coloring agents in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, sodium tragacanth or oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The daily dosage of the products of the present invention can vary over a wide range of 1 to 5000 mg per human adult per day. For oral administration, the compositions are preferably provided in the form of tablets, which contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of a compound of the present invention is ordinarily supplied at a dosage level of about 0.01 mg / kg to about 200 mg / kg of body weight per day. Particularly, the range is from about 0.03 to about 15 mg / kg of body weight per day and more particularly, from about 0.05 to about 10 mg / kg of body weight per day. The compounds of the present invention can be administered at a rate of up to four or more times per day, preferably 1 to 2 times per day.

The optimal dosages to be administered can be readily determined by those skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration and the progress of the disease condition. In addition, the factors associated with the particular patient being treated, including the patient's age, weight, diet and time of administration, will result in the need to adjust the dosages. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, including, but not limited to, amphipathic lipids such as phosphatidylcholines., sphingomyelins, phosphatidylethanolamines, phosphatidylethanolamines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes and stearylamine, neutral lipids such as triglycerides and combinations thereof. They may contain cholesterol or they may be free of cholesterol. Another alternative method for administering the compounds of the invention can be by conjugating a compound to a selection agent that directs the conjugate to its intended site of action, i.e., to vascular endothelial cells, or to tumor cells. Antibody and non-antibody selection agents can be used. Because of the specific interaction between the selection agent and its corresponding binding partner, the compound of the present invention can be administered at high local concentrations at or near a target site and thus treat the disorder at the target site more effectively. Agents that select the antibody include antibodies or fragments that bind to the antigen thereof, which bind to a selectable or accessible component of a tumor cell, the tumor vasculature or a tumor stroma. The "selectable or accessible component" of a tumor cell, the tumor vasculature or a tumor stroma, is preferably a component expressed on the surface, accessible at the surface or located on the surface. Agents that select the antibody also include antibodies or fragments that bind to the antigen thereof, which bind to an intracellular component that is released from a necrotic cell of the tumor. Preferably, such antibodies are monoclonal antibodies or antigen-binding fragments thereof, which bind insoluble intracellular antigens present in cells that can be induced to be permeable, or in phantom cells of substantially all neoplastic cells and normal, but not present or accessible outside of the normal living cells of a mammal. As used herein, the term "antibody" is intended to refer to any immunological binding agent, such as IgG, IgM, IgA, IgE, F (ab ') 2, a univalent fragment such as Fab', Fab, Dab, as well as designed antibodies such as recombinant antibodies, humanized antibodies, bispecific antibodies and the like. The antibody can be polyclonal or monoclonal, although monoclonal is preferred. There is a very broad array of antibodies known in the art to have immunological specificity for the cell surface of virtually any type of solid tumor (see, the Monoclonal Antibody Summary Table for Solid Tumors in U.S. Patent No. 5,855,866). Thorpe et al). Methods are known to those skilled in the art to produce and isolate antibodies against the tumor (see, US Patent No. 5,855,866 to Thorpe et al., And US Patent No. 6,34,2219 to Thorpe. et al.). The techniques for conjugating a therapeutic moiety to the antibodies are well known. (See, for example, Amon et al., "Monoclonal Antibodies for Immunotherapy of Drugs in Cancer Therapy," in Monoclonal Antibodies and Cancer Therapy, Reisfeld et al. (Eds.), Pp. 243-56 (Alan R. Liss, Inc. 1985), Hellstrom et al., "Antibodies for Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (Eds.), Pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review," in Monoclonal Antibodies '84: Biological and Clinical Applications, Pinchera et al. (Eds.), Pp. 475-506 (1985)). Similar techniques can also be applied to bind the compounds of the invention to agents that select non-antibodies. Those with experience in the art will know or be able to determine, the methods to form conjugated with agents that select non-antibodies, such as small molecules, oligopeptides, polysaccharides and other polyanionic compounds. Although any binding moiety that is reasonably stable in the blood can be used to bind the compounds of the present invention to the selection agent, biologically releasable bonds and / or selectively cleavable binders or binders are preferred. The "biologically releasable bonds" and the selectively cleavable binders or binders "still have reasonable stability in the circulation, but are releasable, cleavable or hydrolysable only or preferably under certain conditions, ie, in a certain medium, or in contact with a particular agent, such links include, for example, disulfide and trisulfide bonds and labile bonds with acid, as described in US Patents. Nos. 5,474,765 and 5,762,918 and enzyme-sensitive linkages, including peptide bonds, esters, amides, phosphodiesters and glycosides as described in US Patents. Nos. 5,474,765 and 5,762,918. Such selective release design features facilitate the sustained release of the compounds of the conjugates at the intended target site. The present invention further provides a method for treating a disorder related to C-KIT, particularly a tumor, comprising administering to a subject, a therapeutically effective amount of a compound of the present invention conjugated to a selection agent.

When proteins such as antibodies or growth factors are used, or polysaccharides as the selection agents, they are preferably administered in the form of injectable compositions. The injectable antibody solution will be administered in a vein, artery or spinal fluid in the course of 2 minutes to approximately 45 minutes, preferably 10 to 20 minutes. In certain cases, intradermal administration and intracavity are advantageous for tumors restricted to areas near particular regions of the skin and / or to particular body cavities. In addition, intrathecal administration can be used for tumors located in the brain. A therapeutically effective dose of a compound of the present invention, conjugated to a selection agent depends on the individual, the type of disease, the disease state, the method of administration and other clinical variables. Effective dosages are easily determined using data from animal models, including those presented here. Although the above specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all variations, adaptations and / or customary modifications, since they fall within the scope of the following claims and their equivalents.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - The use of a pharmaceutical composition comprising a compound of Formula I: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl) , -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which can be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1, 2, 4-triazolyl or furanyl may contain a substitution with -Cl, -CN, -N02, -OMe or -CF3, connected to any other carbon; R 2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and C (i-3) alkyl, with the condition that the tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional condition that Qb it may not be -NH- if R3 is an amino group or a cyclic amino radical, wherein the point of attachment to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5- or 6-membered ring can be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl, for the preparation of a medicament useful for treating in a subject a disorder related to FLT3C-KIT. 2. The use as claimed in claim 1, wherein A is phenyl or pyridyl; X is is oriented to with respect to -NHCO-W. 3 - The use as claimed in claim 2, wherein W is 3H-2-imidazolyl-4-carbonitrile. 4. The use as claimed in claim 3, wherein R2 is cyclohexenyl, which may be substituted with one or two methyl groups. 5 - The use as claimed in claim 4, wherein: X is ; Z is CH1 D1 and D2 are each hydrogen; D3 and D4 are each hydrogen; D5 is -CH3, wherein -CH3 can be oriented relatively syn or anti; E is N; Qb is absent, is -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), with the additional condition that Qb may not be - NH- if R3 is an amino group or a cyclic amino radical, wherein the point of binding to Qb is N; and R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-CH3, -NH2, pyridyl, pyridyl-N-oxide or morpholinyl. 6. The use as claimed in claim 5, wherein: X is 7. - The use as claimed in claim 6, wherein the medicament is adapted to be administrable with a chemotherapeutic agent. 8. The use as claimed in claim 6, wherein the medicament is adapted to be administrable with gene therapy. 9. - The use as claimed in claim 6, wherein the medicament is adapted to be administrable with immunotherapy. 10. - The use as claimed in claim 6, wherein the medicament is adapted to be administrable with radiation therapy. 1. A method for reducing the activity of the C-KIT kinase in a cell, comprising the step of contacting the cell with a compound of Formula I: I or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl) , -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which can be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1, 2, 4-triazolyl or furanyl may contain a substitution with -Cl, -CN, -NO2, -OMe or -CF3, connected to any other carbon; R 2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and C (i. 3) alkyl, with the condition that the tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is one hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional condition that Qb it may not be -NH- if R3 is an amino group or a cyclic amino radical, wherein the point of attachment to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a ring of 5 or six members containing at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, S02, N and O, and the 5 or 6 membered ring may be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring it is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl. 12. The use of a compound of Formula I: I or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl) , -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl may contain one substitution with -Cl, -CN, -NO2, -OMe or -CF3, connected to any other carbon; R2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chlorine, fluorine and C (i_3) alkyl, with the condition that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is ; Z is CH or N; D and D2 are each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; Ra and b are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or a cyclic amino radical, in where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional proviso that Qb may not be -NH- if R3 is an amino group or a cyclic amino radical, where the point of binding to Qb is N; R3 is hydrogen, hydroxyalkylamine, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -SO2-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heteroporption selected from S, SO2, N and O, and the 5- or 6-membered ring may be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl; for the preparation of a medicament useful for the treatment of a disorder related to C-KIT in a subject, wherein the medicament is formulated in an intraluminal medical device for controlled delivery. method according to claim characterized further in that the intraluminal medical device comprises a stent. 14. - The use as claimed in claim 12, wherein the intraluminal medical device comprises a stent. 15. - The use of a compound of Formula I: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, any of which may be substituted with one of chlorine, fluorine, methyl, -N3, -NH2, -NH (alkyl) , -N (alkyl) 2, -S (alkyl), -O (alkyl) or 4-aminophenyl, W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl, any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,4-triazolyl or furanyl may contain a substitution with -Cl, -CN, -NO2, -OMe or -CF3, connected to any other carbon; R 2 is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be substituted independently with one or two of each of the following: chlorine, fluorine and C (i-3) alkyl, with the proviso that tetrahydropyridyl is connected to ring A through a carbon-carbon bond; X is each hydrogen or taken together form a double bond with an oxygen; D3 and D4 are each hydrogen or taken together form a double bond with an oxygen; D5 is hydrogen or -CH3, wherein -CH3 can be oriented relatively syn or anti; R a and R are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; E is N, S, O, SO or SO2, with the proviso that E may not be N if the following three conditions are met simultaneously: Qa is absent, Qb is absent, and R3 in an amino group or radical cyclic amino, where the point of attachment to E is N; Qa is absent, is -CH2-, -CH2CH2- or C (O); Qb is absent, is -NH-, -CH2-, -CH2CH2- or C (O), with the proviso that Qb may not be C (O) if Qa is C (O), and with the additional condition that Qb may not be -NH- if E is N and Qa is absent, with the additional condition that Qb it may not be -NH- if R3 is an amino group or a cyclic amino radical, wherein the point of attachment to Qb is N; R3 is hydrogen, hydroxyalkylamino, (hydroxyalkyl) 2-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, -COOH, -CONH2, -CN, -S02-alkyl-R4, -NH2, or a 5 or 6 membered ring which contains at least one heteroatom of N and may optionally contain an additional heterophore selected from S, S02, N and O, and the 5 or 6 membered ring can be saturated, partially unsaturated or aromatic, wherein the aromatic nitrogen in the 5 or 6 membered ring is present as N oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino or alkoxy; R3 may also be absent, provided that R3 is not absent when E is nitrogen; R 4 is hydrogen, -OH, alkoxy, carboxy, carboxamido or carbamoyl; conjugated to a selection agent, for the preparation of a medicament useful for treating a disorder related to C-KIT in a subject. 16. A method for reducing the activity of the C-KIT kinase in a cell, comprising the step of contacting the cell with a compound, the compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 17 - A method for inhibiting the kinase activity of C-KIT in a cell, comprising the step of contacting the cell with a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 18. The use of a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for reducing the activity of the C-KIT kinase in a subject. 19. The use of a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for inhibiting the activity of the C-KIT kinase in a subject. 20. The use of a pharmaceutical composition comprising the compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the preparation of a useful drug to prevent in a subject a disorder related to C-KIT. 21. The use of a pharmaceutical composition comprising a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for the manufacture of a medicament useful for treating in a subject a disorder related to C-KIT. 22. The use as claimed in claim 21, wherein the medicament is adapted to be administrable with a chemotherapeutic agent. 23. - The use as claimed in claim 21, wherein the medicament is adapted to be administrable with gene therapy. 24. - The use as claimed in claim 21, wherein the medicament is adapted to be administrable with immunotherapy. 25. - The use as claimed in claim 21, wherein the medicament is adapted to be administrable with radiation therapy. 26. - The use of a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of a cell proliferative disorder in a subject, wherein the medicament is formulated in an intraluminal medical device for controlled delivery. 27.- The use of a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of a disorder related to C-KIT in a subject, wherein the drug is formulated in an intraluminal medical device for controlled delivery. 28 - The use as claimed in claim 26, wherein the intraluminal medical device comprises a stent. 29. The use as claimed in claim 27, wherein the intraluminal medical device comprises a stent. The use of a compound of the present invention or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, conjugated to a selection agent, for the manufacture of a medicament useful for treating a cell proliferative disorder. 31.- The use of a compound of the present invention: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, conjugated to a selection agent, for the manufacture of a medicament useful for treating a disorder related to C-KIT.